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Smooth Muscle Cell Hypertrophy, Proliferation, Migration and Apoptosis in Pulmonary Hypertension

Tamara Tajsic, Nicholas W. Morrell

10.1002/cphy.c100026

Source: Volume 1, Issue 1, January 2011

Published online: November 2010

Full Article on Wiley Online Library



Abstract

Pulmonary hypertension is a multifactorial disease characterized by sustained elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP). Central to the pathobiology of this disease is the process of vascular remodelling. This process involves structural and functional changes to the normal architecture of the walls of pulmonary arteries (PAs) that lead to increased muscularization of the muscular PAs, muscularization of the peripheral, previously nonmuscular, arteries of the respiratory acinus, formation of neointima, and formation of plexiform lesions. Underlying or contributing to the development of these lesions is hypertrophy, proliferation, migration, and resistance to apoptosis of medial cells and this article is concerned with the cellular and molecular mechanisms of these processes. In the first part of the article we focus on the concept of smooth muscle cell phenotype and the difficulties surrounding the identification and characterization of the cell/cells involved in the remodelling of the vessel media and we review the general mechanisms of cell hypertrophy, proliferation, migration and apoptosis. Then, in the larger part of the article, we review the factors identified thus far to be involved in PH intiation and/or progression and review and discuss their effects on pulmonary artery smooth muscle cells (PASMCs) the predominant cells in the tunica media of PAs. © 2011 American Physiological Society. Compr Physiol 1:295‐317, 2011.

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Figure 1. Figure 1.

Cell hypertrophy is an increase in cell size. Increased protein synthesis and decreased protein degradation result in increased protein content in the cell. Changes in plasmallemmal proteins, such as rise in the expression of the Na+‐K+‐ATPase and the Na+‐K+‐2Cl− cotransporter lead to increased intracellular water content which is critical for the maintenance of increased cell volume. Cell enlargement can be coupled with DNA synthesis. Possible effectors of hypertrophy are G‐protein coupled receptor (GPCR) agonists such as angiotensin II (ANGII), endothelin‐1 (ET‐1) and thromboxane A2 (TXA2), and receptor tyrosine kinases (RTKs).
Figure 2. Figure 2.

The cell cycle is an ordered sequence of events in which a cell duplicates its content (during G1, S, and G2 phases) and divides into two daughter cells (during M phase). The proliferation of human cells is regulated mainly by a variety of growth factors. In a healthy adult, VSMCs are highly differentiated the concentration of the growth factors is low and there is no need for their further replication in normal conditions, so they withdraw from the cell cycle, entering the resting state, that is, G0 phase. In pathological conditions, cells can be stimulated to reenter the cell cycle and replicate.
Figure 3. Figure 3.

Apoptosis is an ordered and regulated process leading to cell death. An apoptotic signal triggers a series of events: first, cell volume decrease (apoptotic volume decrease); second, mitochondrial membrane depolarization leading to cytochrome c release and consequent caspase activation (the effector phase); third, DNA fragmentation and apoptotic body formation (the late phase). Two major apoptotic pathways activate different initiator caspases: caspases 8 and 10 in the extrinsic pathway and caspase 9 in the intrinsic pathways. Activation of different initiator caspases ultimately leads to the activation of the same effector caspases 3, 6, and 7.
Figure 4. Figure 4.

Migration stimulus triggers actin polymerization, which results in the formation of lamellipodia or filopodia at the leading edge of the cell. These structures form stable contacts with the underlying surface enabling the cell to push forward. First, the cytoplasm moves forward followed by the nucleus and the organelles. Finally, the focal adhesions at the rear of the cell are broken enabling retraction of the rear of the cell. PDGF, FGF, EGF, IL‐6, collagen types I and IV, fibronectin, laminin, osteopontin, and thrombospondin are known to promote, whereas heparin and tissue inhibitors of metalloproteinase (TIMP) block VSMC migration.
Figure 5. Figure 5.

Vasoactive substances, growth factors, and cytokines involved in the development and/or progression of PH and their effects on PASMCs. ANG‐1, angiopoietin 1; AngII, angiotensin II; BMPs 2, 4, and 7, bone morphogenetic proteins 2, 4, and 7; CCL2, CC ligand 2; ET‐1, endothelin‐1; EGF, epidermal growth factor; GPCR, G‐protein‐coupled receptor; FGF2, fibroblast growth factor 2; 5‐HT, 5‐hydroxitryptophan, serotonin; IL‐6, interleukin 6; NO, nitric oxide; PDGF, platelet‐derived growth factor; PGI2, prostacyclin; PPAR‐γ, peroxisome proliferator‐activated receptor γ; RTKs, receptor tyrosine kinases; TG2, transglutaminase type 2; Tie2, endothelial‐specific tyrosine kinase; TGF‐β (beta) = transforming growth factor β (beta); TXA2, tromboxane A2; VIP = vasoactive intestinal peptide.
Figure 6. Figure 6.

Effects of calcium and potassium on pulmonary artery smooth muscle cell (PASMCs) and their perturbations in PH. Intracellular cytoplasmic concentration of Ca ([Ca2+]cyt) regulates cell proliferation by stimulating progression of all four phases of the cell cycle, by activating ERK2, and by activating the AP‐1 family of proteins such as c‐jun and c‐fos. Proliferating PASMCs have increased [Ca2+]cyt and increased expression of store‐operated (SOC) channels such as TRPC1, TRPC3, and TRPC6. Potassium channel currents are critical for the maintenance of the resting membrane potential (Em) and important for promoting apoptosis by triggering AVD and releasing of caspases and nucleases and mitochondrial cytochrome c. Decreased expression of K+ channels favors proliferation through membrane depolarization that leads to opening of the voltage‐dependant Ca2+ channels and consequent increase in [Ca2+]cyt and confers resistance to apoptosis.
Figure 7. Figure 7.

Direct and indirect effects of hypoxia on pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and apoptosis. Hypoxia promotes proliferation and resistance to apoptosis of PASMCs directly: by activating GPCR and consequently ERK1/2, by increasing the expression of Ca2+ channels (TRPC1 and TRPC6) causing increased intracellular concentration of Ca and by decreasing the expression of K channels resulting in decreased K currents. Hypoxia affects pulmonary artery endothelial cells causing imbalance in the production of vasoactive factors in favor of the ones that exert mitogenic effects on PASMCS (ET‐1, PDGF, IL‐6, 5‐HT). Hypoxia also affects extracellular matrix production favoring PASMC proliferation and migration.
Figure 8. Figure 8.

In hypertensive pulmonary arteries, as a result of elastase activity, a proteolytic cascade is activated that results in matrix metalloproteinase (MMP) activation and tenascin‐C production and consequent pulmonary artery smooth muscle cell proliferation and migration. EVE, endogenous vascular elastase; FGF2, fibroblast growth factor 2; ECM, extracellular matrix; EGF, epidermal growth factor.


Figure 1.

Cell hypertrophy is an increase in cell size. Increased protein synthesis and decreased protein degradation result in increased protein content in the cell. Changes in plasmallemmal proteins, such as rise in the expression of the Na+‐K+‐ATPase and the Na+‐K+‐2Cl− cotransporter lead to increased intracellular water content which is critical for the maintenance of increased cell volume. Cell enlargement can be coupled with DNA synthesis. Possible effectors of hypertrophy are G‐protein coupled receptor (GPCR) agonists such as angiotensin II (ANGII), endothelin‐1 (ET‐1) and thromboxane A2 (TXA2), and receptor tyrosine kinases (RTKs).



Figure 2.

The cell cycle is an ordered sequence of events in which a cell duplicates its content (during G1, S, and G2 phases) and divides into two daughter cells (during M phase). The proliferation of human cells is regulated mainly by a variety of growth factors. In a healthy adult, VSMCs are highly differentiated the concentration of the growth factors is low and there is no need for their further replication in normal conditions, so they withdraw from the cell cycle, entering the resting state, that is, G0 phase. In pathological conditions, cells can be stimulated to reenter the cell cycle and replicate.



Figure 3.

Apoptosis is an ordered and regulated process leading to cell death. An apoptotic signal triggers a series of events: first, cell volume decrease (apoptotic volume decrease); second, mitochondrial membrane depolarization leading to cytochrome c release and consequent caspase activation (the effector phase); third, DNA fragmentation and apoptotic body formation (the late phase). Two major apoptotic pathways activate different initiator caspases: caspases 8 and 10 in the extrinsic pathway and caspase 9 in the intrinsic pathways. Activation of different initiator caspases ultimately leads to the activation of the same effector caspases 3, 6, and 7.



Figure 4.

Migration stimulus triggers actin polymerization, which results in the formation of lamellipodia or filopodia at the leading edge of the cell. These structures form stable contacts with the underlying surface enabling the cell to push forward. First, the cytoplasm moves forward followed by the nucleus and the organelles. Finally, the focal adhesions at the rear of the cell are broken enabling retraction of the rear of the cell. PDGF, FGF, EGF, IL‐6, collagen types I and IV, fibronectin, laminin, osteopontin, and thrombospondin are known to promote, whereas heparin and tissue inhibitors of metalloproteinase (TIMP) block VSMC migration.



Figure 5.

Vasoactive substances, growth factors, and cytokines involved in the development and/or progression of PH and their effects on PASMCs. ANG‐1, angiopoietin 1; AngII, angiotensin II; BMPs 2, 4, and 7, bone morphogenetic proteins 2, 4, and 7; CCL2, CC ligand 2; ET‐1, endothelin‐1; EGF, epidermal growth factor; GPCR, G‐protein‐coupled receptor; FGF2, fibroblast growth factor 2; 5‐HT, 5‐hydroxitryptophan, serotonin; IL‐6, interleukin 6; NO, nitric oxide; PDGF, platelet‐derived growth factor; PGI2, prostacyclin; PPAR‐γ, peroxisome proliferator‐activated receptor γ; RTKs, receptor tyrosine kinases; TG2, transglutaminase type 2; Tie2, endothelial‐specific tyrosine kinase; TGF‐β (beta) = transforming growth factor β (beta); TXA2, tromboxane A2; VIP = vasoactive intestinal peptide.



Figure 6.

Effects of calcium and potassium on pulmonary artery smooth muscle cell (PASMCs) and their perturbations in PH. Intracellular cytoplasmic concentration of Ca ([Ca2+]cyt) regulates cell proliferation by stimulating progression of all four phases of the cell cycle, by activating ERK2, and by activating the AP‐1 family of proteins such as c‐jun and c‐fos. Proliferating PASMCs have increased [Ca2+]cyt and increased expression of store‐operated (SOC) channels such as TRPC1, TRPC3, and TRPC6. Potassium channel currents are critical for the maintenance of the resting membrane potential (Em) and important for promoting apoptosis by triggering AVD and releasing of caspases and nucleases and mitochondrial cytochrome c. Decreased expression of K+ channels favors proliferation through membrane depolarization that leads to opening of the voltage‐dependant Ca2+ channels and consequent increase in [Ca2+]cyt and confers resistance to apoptosis.



Figure 7.

Direct and indirect effects of hypoxia on pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and apoptosis. Hypoxia promotes proliferation and resistance to apoptosis of PASMCs directly: by activating GPCR and consequently ERK1/2, by increasing the expression of Ca2+ channels (TRPC1 and TRPC6) causing increased intracellular concentration of Ca and by decreasing the expression of K channels resulting in decreased K currents. Hypoxia affects pulmonary artery endothelial cells causing imbalance in the production of vasoactive factors in favor of the ones that exert mitogenic effects on PASMCS (ET‐1, PDGF, IL‐6, 5‐HT). Hypoxia also affects extracellular matrix production favoring PASMC proliferation and migration.



Figure 8.

In hypertensive pulmonary arteries, as a result of elastase activity, a proteolytic cascade is activated that results in matrix metalloproteinase (MMP) activation and tenascin‐C production and consequent pulmonary artery smooth muscle cell proliferation and migration. EVE, endogenous vascular elastase; FGF2, fibroblast growth factor 2; ECM, extracellular matrix; EGF, epidermal growth factor.

 1. Aaronson PI, Robertson TP, Ward JP. Endothelium‐derived mediators and hypoxic pulmonary vasoconstriction. Respir Physiol Neurobiol 132: 107‐120, 2002.
 2. Adnot S. Lessons learned from cancer may help in the treatment of pulmonary hypertension. J Clin Invest 115: 1461‐1463, 2005.
 3. Ambalavanan N, Mariani G, Bulger A, Philips JB III. Role of nitric oxide in regulating neonatal porcine pulmonary artery smooth muscle cell proliferation. Biol Neonate 76: 291‐300, 1999.
 4. Ameshima S, Golpon H, Cool CD, Chan D, Vandivier RW, Gardai SJ, Wick M, Nemenoff RA, Geraci MW, Voelkel NF. Peroxisome proliferator‐activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res 92(10): 1162‐1169, 2003.
 5. Archer SL. Diversity of phenotype and function of vascular smooth muscle cells. J Lab Clin Med 127: 524‐529, 1996.
 6. Archer SL. Pre‐B‐cell colony‐enhancing factor regulates vascular smooth muscle maturation through a NAD‐dependent mechanism: Recognition of a new mechanism for cell diversity and redox regulation of vascular tone and remodeling. Circ Res 97: 4‐7, 2005.
 7. Archer SL, Weir EK, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians: New concepts and experimental therapies. Circulation 121(18): 2045‐2066, 2010.
 8. Arcot SS, Fagerland JA, Lipke DW, Gillespie MN, Olson JW. Basic fibroblast growth factor alterations during development of monocrotaline‐induced pulmonary hypertension in rats. Growth Factors 12: 121‐130, 1995.
 9. Arimura C, Suzuki T, Yanagisawa M, Imamura M, Hamada Y, Masaki T. Primary structure of chicken skeletal muscle and fibroblast alpha‐actinins deduced from cDNA sequences. Eur J Biochem 177: 649‐655, 1988.
 10. Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M, Takahashi M, Nakamura T, Shimomura I, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Adipocyte‐derived plasma protein adiponectin acts as a platelet‐derived growth factor‐BB‐binding protein and regulates growth factor‐ induced common postreceptor signal in vascular smooth muscle cell. Circulation 105: 2893‐2898, 2002.
 11. Atkinson C, Stewart S, Upton PD, Machado R, Thomson JR, Trembath RC, Morrell NW. Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105: 1672‐1678, 2002.
 12. Au YP, Kenagy RD, Clowes MM, Clowes AW. Mechanisms of inhibition by heparin of vascular smooth muscle cell proliferation and migration. Haemostasis 23(Suppl 1): 177‐182, 1993.
 13. Babij P, Kelly C, Periasamy M. Characterization of a mammalian smooth muscle myosin heavy‐chain gene: Complete nucleotide and protein coding sequence and analysis of the 5′ end of the gene. Proc Natl Acad Sci USA 88: 10676‐10681, 1991.
 14. Badesch DB, Orton EC, Zapp LM, Westcott JY, Hester J, Voelkel NF, Stenmark KR. Decreased arterial wall prostaglandin production in neonatal calves with severe chronic pulmonary hypertension. Am J Respir Cell Mol Biol 1: 489‐498, 1989.
 15. Balabanian K, Foussat A, Dorfmuller P, Durand‐Gasselin I, Capel F, Bouchet‐Delbos L, Portier A, Marfaing‐Koka A, Krzysiek R, Rimaniol AC, Simonneau G, Emilie D, Humbert M. CX(3)C chemokine fractalkine in pulmonary arterial hypertension. Am J Respir Crit Care Med 165(10): 1419‐1425, 2002.
 16. Balasubramaniam V, Le Cras TD, Ivy DD, Grover TR, Kinsella JP, Abman SH. Role of platelet derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 284: L826‐L833, 2003.
 17. Barnes PJ, Belvisi MG. Nitric oxide and lung disease. Thorax 48(10): 1034‐43, 1993.
 18. Bar‐Saqi D, Hall A. Ras and Rho GTPases: A family reunion. Cell 103(2): 193‐200, 2000.
 19. Benezra M, Vlodavsky I, Ishai‐Michaeli R, Neufeld G, Bar‐Shavit R. Thrombin induced release of active basic fibroblast growth factor‐heparan sulfate complexes from subendothelial extracellular matrix. Blood 81: 3324‐3331, 1993.
 20. Benisty JI, McLaughlin VV, Landzberg MJ, Rich JD, Newburger JW, Rich S, Folkman J. Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension. Chest 126: 1255‐1261, 2004.
 21. Benitz WE, Coulson JD, Lessler DS, Bernfield M. Hypoxia inhibits proliferation of fetal pulmonary arterial smooth muscle cells in vitro. Pediatr Res 20: 966‐972, 1986.
 22. Benzakour O, Kanthou C, Kanse SM, Scully MF, Kakkar VV, Cooper DN. Evidence for cultured human vascular smooth muscle cell heterogeneity: Isolation of clonal cells and study of their growth characteristics. Thromb Haemostasis 75: 854‐858, 1996.
 23. Berk BC. Vascular smooth muscle growth: Autocrine growth mechanisms. Physiol Rev 81(3): 999‐1030, 2001.
 24. Berk BC, Vekshtein V, Gordon HM, Tsuda T. Angiotensin II‐stimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension 13: 305‐314, 1989.
 25. Berridge MJ. Inositol triphosphate and calcium signaling. Nature 361: 315‐325, 1993.
 26. Black MJ, Adams MA, Bobik A, Campbell JH, Campbell GR. Effect of enalapril on aortic smooth muscle cell polyploidy in the spontaneously hypertensive rat. J Hypertens 7: 997‐1003, 1989.
 27. Blaustein MP, Lederer WJ. Sodium/calcium exchange: Its physiological implications. Physiol Rev 79: 763‐854, 1999.
 28. Bolmont C, Lilienbaum A, Paulin D, Grimaud JA. Expression of the desmin gene in skeletal and smooth muscle by in situ hybridization using a human desmin gene probe. J Submicrosc Cytol Pathol 22: 117‐122, 1990.
 29. Borrione AC, Zanellato AM, Giuriato L, Scannapieco G, Pauletto P, Sartore S. Nonmuscle and smooth muscle myosin isoforms in bovine endothelial cells. Exp Cell Res 190: 1‐10, 1990.
 30. Bortner CD, Cidlowski JA. Caspase independent/dependent regulation of K(+), cell shrinkage, and mitochondrial membrane potential during lymphocyte apoptosis. J Biol Chem 274(31): 21953‐21962, 1999.
 31. Boucher P, Gotthardt M. LRP and PDGF signaling: A pathway to atherosclerosis. Trends Cardiovasc Med 14: 55‐60, 2004.
 32. Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J. LRP: Role in vascular wall integrity and protection from atherosclerosis. Science 300: 329‐332, 2003.
 33. Buczek‐Thomas JA, Nugent MA. Elastase‐mediated release of heparan sulfate proteoglycans from pulmonary fibroblast cultures. A mechanism for basic fibroblast growth factor (bFGF) release and attenuation of bfgf binding following elastase‐induced injury. J Biol Chem 274: 25167‐25172, 1999.
 34. Burg ED, Remillard CV, Yuan JX. Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: Pharmacotherapeutic implications. Br J Pharmacol 153(Suppl 1): S99‐S111, 2008.
 35. Burridge K, Chrzanowska‐Wodnicka M. Focal adhesions, contractility, and signaling. Annu Rev Cell Dev Biol 12: 463‐518, 1996.
 36. Cell cycle control and cell death. In: Alberts A, Bray D, Hopkin K, Johnson A, Lewis J, Raff M, Roberts K, Walter P, editors. Essential Cell Biology. 2nd ed. New York: Garland Science, 2004, p. 609‐636.
 37. Chamley‐Campbell JH, Campbell GR, Ross R. Phenotype‐dependent response of cultured aortic smooth muscle to serum mitogens. J Cell Biol 89: 379‐383, 1981.
 38. Chaouat A, Coulet F, Favre C, Simonneau G, Weitzenblum E, Soubrier F, Humbert M. Endoglin germline mutation in a patient with hereditary hemorrhagic telangiectasia and dexfenfluramine‐associated pulmonary arterial hypertension. Thorax 59: 446‐448, 2004.
 39. Chapman GB, Durante W, Hellums JD, Schafer AI. Physiological cyclic stretch causes cell cycle arrest in cultured vascular smooth muscle cells. Am Jour Physiol Heart Circ Physiol 278: H748‐H754, 2000.
 40. Chen YF, Oparil S. Endothelin and pulmonary hypertension. J Cardiovasc Pharmacol 35(4)(Suppl 2): S49‐S53, 2000.
 41. Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, Loyd, JE. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 32: 70‐75, 1992.
 42. Chu D, Sullivan CC, Du L, Cho AJ, Kido M, Wolf PL, Weitzman MD, Jamieson SW, Thistlethwaite PA. A new animal model for pulmonary hypertension based on the overexpression of a single gene, angiopoietin‐1. Ann Thorac Surg 77: 449‐56, 2004.
 43. Cooper A, Beasley D. Hypoxia stimulates proliferation and interleukin‐1a production in human vascular smooth muscle cells. Am J Physiol 277: H1326‐H1337, 1999.
 44. Cowan KN, Jones PL, Rabinovitch M. Elastase and matrix metalloproteinase inhibitors induce regression, and tenascin‐C antisense prevents progression, of vascular disease. J Clin Invest 105: 21‐34, 2000.
 45. Critchley DR. Focal adhesions—the cytoskeletal connection. Curr Opin Cell Biol 12: 133‐139, 2000.
 46. Dahal BK, Cornitescu T, Tretyn A, Pullamsetti SS, Kosanovic D, Dumitrascu R, Ghofrani HA, Weissmann N, Voswinckel R, Banat GA, Seeger W, Grimminger F, Schermuly RT. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am J Respir Crit Care Med 181(2): 158‐167, 2009.
 47. Dallaporta B, Hirsch T, Susin SA, Zamzami N, Larochette N, Brenner C, Marzo I, Kroemer G. Potassium leakage during the apoptotic degradation phase. J Immunol 160(11): 5605‐5615, 1998.
 48. Datta SR, Brunet A, Greeberg ME. Cellular survival: A play in three Akts. Genes Dev 13(22): 2905‐2927, 1999.
 49. Davie N, Haleen SJ, Upton PD, Polak JM, Yacoub MH, Morrell NW, Wharton J. ETA and ETB receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am J Respir Crit Care Med 165: 398‐405, 2002.
 50. Dempsey EC, Frid MG, Aldashev AA, Das M, Stenmark KR. Heterogeneity in the proliferative response of bovine pulmonary artery smooth muscle cells to mitogens and hypoxia: Importance of protein kinase C. Can J Physiol Pharmacol 75: 936‐944, 1997.
 51. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, Hodge SE, Knowles JA. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor‐II gene. Am J Hum Genet 67: 737‐744, 2000.
 52. Dewachter L, Adnot S, Fadel E, Humbert M, Maitre B, Barlier‐Mur AM, Simonneau G, Hamon M, Naeije R, Eddahibi S. Angiopoietin/Tie2 pathway influences smooth muscle hyperplasia in idiopathic pulmonary hypertension. Am J Respir Crit Care Med 174: 1025‐1033, 2006.
 53. Distelhorst CW. Evidence that BCL‐2 represses apoptosis by regulating endoplasmic reticulum‐associated Ca2+ fluxes. Proc Natl Acad Sci USA 91: 6569‐6573, 1994.
 54. Dorfmuller P, Zarka V, Durand‐Gasselin I, Monti G, Balabanian K, Garcia G, Capron F, Coulomb‐Lhermine A, Marfaing‐Koka A, Simonneau G, Emilie D, Humbert M. Chemokine RANTES in severe pulmonary arterial hypertension. Am J Respir Crit Care Med 165(4): 534‐539, 2002.
 55. Du L, Sullivan CC, Chu D, Cho AJ, Kido M, Wolf PL, Yuan JX, Deutsch R, Jamieson SW, Thistlethwaite PA. Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med 348: 500‐509, 2003.
 56. Duan Sheng Zhong, Usher Michael G, Mortensen Richard M, Rangwala SM, Lazar MA. Peroxisome proliferator‐activated receptor‐mediated effects in the vasculature peroxisome proliferator‐activated receptor gamma in diabetes and metabolism. Trends Pharmacol Sci 25: 331‐336, 2004.
 57. Duband JL, Gimona M, Scatena M, Sartore S, Small JV. Calponin and SM 22 as differentiation markers of smooth muscle: Spatiotemporal distribution during avian embryonic development. Differentiation 55: 1‐11, 1993.
 58. Dubin D, Pratt RE, Kooke JP, Dzau VJ. Endothelin, a potent vasoconstrictor, is a vascular smooth muscle cell mitogen. J Vasc Biol Med 1: 150‐154, 1989.
 59. Eddahibi S, Fabre V, Boni C, Martres MP, Raffestin B, Hamon M, Adnot S. Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle cells: Relationship with the mitogenic action of serotonin. Circ Res 84(3): 329‐336, 1999.
 60. Eddahibi S, Guignabert C, Barlier‐Mur AM, Dewachter L, Fadel E, Dartevelle P, Humbert M, Simonneau G, Hanoun N, Saurini F, Hamon M, Adnot S. Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: Critical role for serotonin‐induced smooth muscle hyperplasia. Circulation 113: 1857‐1864, 2006.
 61. Eddahibi S, Hanoun N, Lanfumey L, Lesch KP, Raffestin B, Hamon M, Adnot S. Attenuated hypoxic pulmonary hypertension in mice lacking the 5‐hydroxytryptamine transporter gene. J Clin Invest 105: 1555‐1562, 2000.
 62. Eddahibi S, Humbert M, Fadel E, Raffestin B, Darmon M, Capron F, Simonneau G, Dartevelle P, Hamon M, Adnot S. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 108(8): 1141‐1150, 2001.
 63. Ekhterae D, Platoshyn O, Krick S, Yu Y, McDaniel SS, Yuan JXJ. Bcl‐2 decreases voltage‐gated K+ channel activity and enhances survival in vascular smooth muscle cells. Am J Physiol Cell Physiol 281: C157‐C165, 2001.
 64. Faller DV. Endothelial cell responses to hypoxic stress. Clin Exp Pharmacol Physiol 26: 74‐84, 1992.
 65. Fanburg BL, Lee SL. A new role for an old molecule: serotonin as a mitogen. Am J Physiol 272(5, Pt 1): L795‐L806, 1997.
 66. Fantozzi I, Platoshyn O, Wong AH, Zhang S, Remillard CV, Furtado MR, Petrauskene OV, Yuan JX. Bone morphogenetic protein‐2 upregulates expression and function of voltage‐gated K+ channels in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 291(5): L993‐L1004, 2006.
 67. Fatigati V, Murphy RA. Actin and tropomyosin variants in smooth muscles. Dependence on tissue type. J Biol Chem 259: 14383‐14388, 1984.
 68. Feinberg MW, Watanabe M, Lebedeva MA, Depina AS, Hanai J, Mammoto T, Frederick JP, Wang XF, Sukhatme VP, Jain MK. Transforming growth factor‐β1 inhibition of vascular smooth muscle cell activation is mediated via Smad3. J Biol Chem 279: 16388‐16393, 2004.
 69. Forough R, Koyama N, Hasenstab D, Lea H, Clowes M, Nikkari ST, Clowes AW. Overexpression of tissue inhibitor of matrix metalloproteinase‐1 inhibits vascular smooth muscle cell functions in vitro and in vivo. Circ Res 79: 812‐820, 1996.
 70. Frank DB, Abtahi A, Yamaguchi DJ, Manning S, Shyr Y, Pozzi A, Baldwin HS, Johnson JE, de Caestecker MP. Bone morphogenetic protein 4 promotes pulmonary vascular remodelling in hypoxic pulmonary hypertension. Circ Res 97: 496‐504, 2005.
 71. Frid MG, Aldashev AA, Dempsey EC, Stenmark KR. Smooth muscle cells isolated from discrete compartments of the mature vascular media exhibit unique phenotypes and distinct growth capabilities. Circ Res 81(6): 940‐952, 1997.
 72. Frid MG, Aldashev AA, Nemenoff RA, Higashito R, Westcott JY, Stenmark KR. Subendothelial cells from normal bovine arteries exhibit autonomous growth and constitutively activated intracellular signaling. Arterioscler Thromb Vasc Biol 19: 2884‐2893, 1999.
 73. Frid MG, Davie NJ, Stenmark KR. Heterogeneity in Hypoxia‐Induced Pulmonary Artery Smooth Muscle Cell Proliferation. Boston: Kluwer Academic Publishers, 2004.
 74. Frid MG, Dempsey EC, Durmowicz AG, Stenmark KR. Smooth muscle cell heterogeneity in pulmonary and systemic vessels: Importance in vascular disease. Arterioscler Thromb Vasc Biol 17: 1203‐1209, 1997.
 75. Frid MG, Li M, Gnanasekharan M, Burke DL, Fragoso M, Strassheim D, Sylman JL, Stenmark KR. Sustained hypoxia leads to the emergence of cells with enhanced growth, migratory, and promitogenic potentials within the distal pulmonary artery wall. Am J Physiol Lung Cell Mol Physiol 297(6): L1059‐L1072, 2009.
 76. Frid MG, Moiseeva EP, Stenmark KR. Multiple phenotypically distinct smooth muscle cell populations exist in the adult and developing bovine pulmonary arterial wall. Circ Res 75: 669‐681, 1994.
 77. Frid MG, Printesva OY, Chiavegato A, Faggin E, Scatena M, Koteliansky VE, Pauletto P, Glukhova MA, Sartore S. Myosin heavy‐chain isoform composition and distribution in developing and adult human aortic smooth muscle. J Vasc Res 30: 279‐292, 1993.
 78. Frisdal E, Gest V, Vieillard‐Baron A, Levame M, Lepetit H, Eddahibi S, Lafuma C, Harf A, Adnot S, Dortho MP. Gelatinase expression in pulmonary arteries during experimental pulmonary hypertension. Eur Respir J 18: 838‐45, 2001.
 79. Fukuda N, Hu WY, Teng J, Chikara S, Nakayama M, Kishioka H, Kanmatsuse K. Troglitazone inhibits growth and improves insulin signalling by suppression of angiotensin II action in vascular smooth muscle cells from spontaneously hypertensive rats. Atherosclerosis 163: 229‐239, 2002.
 80. Gabbiani G, Schmid E, Winter S, Chaponnier C, De Chastonay C, Vandekerckhove J, Weber K, Franke W. Vascular smooth muscle cells differ from other smooth muscle cells: Predominance of vimentin filaments and a specific‐type actin. Proc Natl Acad Sci USA 78: 298‐300, 1981.
 81. Galis ZS, Johnson C, Godin D, Magid R, Shipley JM, Senior RM, Ivan E. Targeted disruption of the matrix metalloproteinase‐9 gene impairs smooth muscle cell migration and geometrical arterial remodeling. Circ Res 91: 852‐859, 2002.
 82. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: The good, the bad, and the ugly. Circ Res 90(3): 251‐262, 2002.
 83. Gauthier A, Vassiliou G, Benoist F, McPherson R. Adipocyte low density lipoprotein receptor‐related protein gene expression and function is regulated by peroxisome proliferator‐activated receptor gamma. J Biol Chem 278: 11945‐11953, 2003.
 84. Geisterfer AAT, Peach MJ, Owens GK. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res 62: 749‐756, 1988.
 85. George SJ, Johnson JL, Angelini GD, Newby AC, Baker AH. Adenovirus‐mediated gene transfer of the human TIMP‐1 gene inhibits smooth muscle cell migration and neointimal formation in human saphenous vein. Hum Gene Ther 9: 867‐877, 1998.
 86. George SJ, Johnson JL, Smith MA, Jackson CL. Plasmin‐mediated fibroblast growth factor‐2 mobilisation supports smooth muscle cell proliferation in human saphenous vein. J Vasc Res 38: 492‐501, 2001.
 87. Geraci M, Moore M, Gesell T, Yeager M, Alger L, Golpon H, Gao B, Loyd J, Tuder R, Voelkel N. Gene expression patterns in the lungs of patients with primary pulmonary hypertension: A gene microarray analysis. Circ Res 88: 555‐562, 2001.
 88. Gerasimovskaya EV, Ahmad S, White CW, Jones PL, Carpenter TC, Stenmark KR. Extracellular ATP is an autocrine/paracrine regulator of hypoxia‐induced adventitial fibroblast growth. Signaling through extracellular signal‐regulated kinase‐1/2 and the Egr‐1 transcription factor. J Biol Chem 277: 44638‐44650, 2002.
 89. Gerthoffer WT. Mechanisms of vascular smooth muscle cell migration. Circ Res 100: 607‐621, 2007.
 90. Giaid A. Nitric oxide and endothelin‐1 in pulmonary hypertension. Chest 114: 208S‐212S, 1998.
 91. Giaid A, Saleh D. Reduced expression of nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 333: 214‐221, 1995.
 92. Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib A, Kimura S, Masaki T, Duguid WP, Stewart DJ. Expression of endothelin‐1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328: 1732‐1739, 1993.
 93. Gimona M, Furst DO, Small JV. Metavinculin and vinculin from mammalian smooth muscle: Bulk isolation and characterization. J Muscle Res Cell Motil 8: 329‐341, 1987.
 94. Goetze S, Kim S, Xi XP, Graf K, Yang DC, Fleck E, Meehan WP, Hsueh WA, Law RE. Troglitazone inhibits mitogenic signaling by insulin in vascular smooth muscle cells. J Cardiovasc Pharmacol 35: 749‐757, 2000.
 95. Goetze S, Xi XP, Kawano H, Gotlibowski T, Fleck E, Hsueh WA, Law RE. PPAR gamma‐ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells. J Cardiovasc Pharmacol 33: 798‐806, 1999.
 96. Goldman J, Zhong L, Liu SQ. Degradation of alpha‐actin filaments in venous smooth muscle cells in response to mechanical stretch. Am J Physiol Heart Circ Physiol 284: H1839‐H1847, 2003.
 97. Golembeski SM, West J, Tada Y, Fagan KA. Interleukin‐6 causes mild pulmonary hypertension and augments hypoxia induced pulmonary hypertension in mice. Chest 128(6 Suppl): 572S‐573S, 2005.
 98. Golovina VA, Platoshyn O, Bailey CL, Wang J, Limsuwan A, Sweeney M, Rubin LJ, Yuan JX. Upregulated TRP and enhanced capacitative Ca2+ entry in human pulmonary artery myocytes during proliferation. Am J Physiol: Heart Circ Physiol 280: H746‐H755, 2001.
 99. Goumans M‐J, Liu Z, ten Dijke P. TGFbeta signalling in vascular biology and dysfunction. Cell Res 19: 116‐127, 2009.
 100. Greenway A, van Suylen RJ, Du M, Sarvaas G, Kwan E, Ambartsumian N, Lukanidin E, Rabinovitch M. S100A4/Mts1 produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. Am J Pathol 164: 253‐262, 2004.
 101. Guignabert C, Alvira CM, Alastalo TP, Sawada H, Hansmann G, Zhao M, Wang L, El‐Bizri N, Rabinovitch M. Tie2‐mediated loss of peroxisome proliferator‐activated receptor‐{gamma} in mice causes PDGF receptor‐{beta}‐dependent pulmonary arterial muscularization. Am J Physiol Lung Cell Mol Physiol 297(6): L1082‐L1090, 2009.
 102. Guignabert C, Raffestin B, Benferhat R, Raoul W, Zadigue P, Rideau D, Hamon M, Adnot S, Eddahibi S. Serotonin transporter inhibition prevents and reverses monocrotaline‐induced pulmonary hypertension in rats. Circulation 111: 2812‐2819, 2005.
 103. Guilluy C, Eddahibi S, Agard C, Guignabert C, Izziki M, Tu L, Savale L, Humbert M, Fadel E, Adnot S, Loirand G, Pacaud P. RhoA and Rho kinase activation in human pulmonary hypertension. Am J Respir Crit Care Med 179: 1151‐1158, 2009.
 104. Guilluy C, Rolli‐Derkinderen M, Tharaux PL, Melino G, Pacaud P, Loirand G. Transglutaminase‐dependent RhoA activation and depletion by serotonin in vascular smooth muscle cells. J Biol Chem 282: 2918‐2928, 2007.
 105. Gustafsson AB, Gottlieb RA. Bcl‐2 family members and apoptosis, taken to heart. Am J Physiol Cell Physiol 292: C45‐C51, 2007.
 106. Halka AT, Turner NJ, Carter A, Ghosh J, Murphy MO, Kirton JP, Kielty CM, Walker MG. The effects of stretch on vascular smooth muscle cell phenotype in vitro. Cardiovasc Pathol 17(2): 98‐102, 2008.
 107. Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekker JM, Schellong S, Urashima T, Wang L, Morrell NW, Rabinovitch M. An antiproliferative BMP‐2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest 118: 1846‐57, 2008.
 108. Hardingham GE, Chawla S, Johnson CM, Bading H. Distinct functions of nuclear and cytoplasmic calcium in the control of gene expression. Nature 385: 260‐265, 1997.
 109. Hardingham GE, Cruzalegui FH, Chawla S, Bading H. Mechanisms controlling gene expression by nuclear calcium signals. Cell Calcium 23: 131‐134, 1998.
 110. Hassoun PM, Mouthon L, Barberà JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morrell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX, Humbert M. Inflammation, growth factors, and pulmonary vascular remodelling. J Am Coll Cardiol 54(1)(Suppl): S10‐S19, 2009.
 111. Haunstetter A, Izumo S. Apoptosis: Basic mechanisms and implications for cardiovascular disease. Circ Res 82: 1111‐1129, 1998.
 112. He H, Lam M, McCormick TS, Distelhorst CW. Maintenance of calcium homeostasis in the endoplasmic reticulum by Bcl‐2. J Cell Biol 138: 1219‐1228, 1997.
 113. Hedin U, Bottger BA, Forsberg E, Johansson S, Thyberg J. Diverse effects of fibronectin and laminin on phenotypic properties of cultured arterial smooth muscle cells. J Cell Biol 107: 307‐319, 1988.
 114. Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet‐derived growth factor. Physiol Rev 79: 1283‐1316, 1999.
 115. Herget J, Wilhelm J, Novotna J, Eckhardt A, Vytásek R, Mrázková L, Ostádal M. A possible role of the oxidant tissue injury in the development of hypoxic pulmonary hypertension. Physiol Res 49: 493‐501, 2000.
 116. Herve P, Drouet L, Dosquet C, Launay JM, Rain B, Simonneau G, Caen J, Duroux P. Primary pulmonary hypertension in a patient with a familial platelet storage pool disease: Role of serotonin. Am J Med 89(1): 117‐120, 1990.
 117. Herve P, Launay JM, Scrobohaci ML, Brenot F, Simonneau G, Petitpretz P, Poubeau P, Cerrina J, Duroux P, Drouet L. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99(3): 249‐254, 1995.
 118. Higashiyama S, Abraham JA, Klagsbrun M. Heparin‐binding EGF‐like growth factor stimulation of smooth muscle cell migration: Dependence on interactions with cell surface heparan sulfate. J Cell Biol 122: 933‐940, 1993.
 119. Hill C. Nucleocytoplasmic shuttling of Smad proteins. Cell Res 19: 36‐46, 2009.
 120. Hislop A, Reid L. New findings in pulmonary arteries of rats with hypoxia‐induced pulmonary hypertension. Br J Exp Pathol 57(5): 542‐554, 1976.
 121. Hu Y, Bock G, Wick G, Xu Q. Activation of PDGF receptor alpha in vascular smooth muscle cells by mechanical stress. FASEB J 12: 1135‐1142, 1998.
 122. Hughes FM Jr, Bortner CD, Purdy GD, Cidlowski JA. Intracellular K+ suppresses the activation of apoptosis in lymphocytes. J Biol Chem 272(48): 30567‐30576, 1997.
 123. Humbert M, Montani D, Perros F, Dorfmüller P, Adnot S, Eddahibi S. Endothelial cell dysfunction and cross talk between endothelium and smooth muscle cells in pulmonary arterial hypertension. Vasc Pharmacol 49(4–6): 113‐118, 2008.
 124. Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot‐Keros L, Duroux P, Galanaud P, Simonneau G, Emilie D. Increased interleukin‐1 and interleukin‐6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 151(5): 1628‐1631, 1995.
 125. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43(12)(Suppl S): 13S‐24S, 2004.
 126. Hungerford JE, Owens GK, Argraves WS, Little CD. Development of the aortic vessel wall as defined by vascular smooth muscle and extracellular matrix markers. Dev Biol 178: 375‐392, 1996.
 127. Hunter T. Signaling—2000 and beyond. Cell 100(1): 113‐127, 2000.
 128. Ihida‐Stansbury K, McKean DM, Lane KB, Loyd JE, Wheeler LA, Morrell NW, Lloyd Jones P. Tenascin‐C is induced by mutated BMP type II receptors in familial forms of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 291: 694‐702, 2006.
 129. International PPH Consortium, Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA III, Loyd JE, Nichols WC, Trembath RC. Heterozygous germline mutations in BMPR2, encoding a TGF‐beta receptor, cause familial primary pulmonary hypertension. Nat Genet 26: 81‐84, 2000.
 130. Itoh H, Mukoyama M, Pratt RE, Gibbons GH, Dzau VJ. Multiple autocrine growth factors modulate vascular smooth muscle cell growth response to angiotensin II. J Clin Invest 91: 2268‐2274, 1993.
 131. Itoh H, Pratt IH, Dzau VJ. Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells. J Clin Invest 86: 1690‐1697, 1990.
 132. Itoh T, Nagaya N, Ishibashi‐Ueda H, Kyotani S, Oya H, Sakamaki F, Kimura H, Nakanishi N. Increased plasma monocyte chemoattractant protein‐1 level in idiopathic pulmonary arterial hypertension. Respirology 11(2): 158‐163, 2006.
 133. Iwasaki H, Eguchi S, Ueno H, Marumo F, Hirata Y. Mechanical stretch stimulates growth of vascular smooth muscle cells via epidermal growth factor receptor. Am Jour Physiol Heart Circ Physiol 278: H521‐H529, 2000.
 134. Izikki M, Guignabert C, Fadel E, Humbert M, Tu L, Zadigue P, Dartevelle P, Simonneau G, Adnot S, Maitre B, Raffestin B, Eddahibi S. Endothelial‐derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 119(3): 512‐523.
 135. Jackson CL, Raines EW, Ross R, Reidy MA. Role of endogenous platelet‐derived growth factor in arterial smooth muscle cell migration after balloon catheter injury. Arterioscler Thromb 13: 1218‐1226, 1993.
 136. Jones PL, Cowan KN, Rabinovitch M. Induction of tenascin and fibronectin are features associated with increased smooth muscle cell proliferation during the development of progressive pulmonary hypertension in children. Am J Pathol 150: 1349‐1360, 1997a.
 137. Jones PL, Cowan KN, Rabinovitch M. Tenascin‐C, proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol 150(4): 1349‐1360, 1997b.
 138. Jones PL, Crack J, Rabinovitch M. Regulation of tenascin‐C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J Cell Biol 139(1): 279‐293, 1997.
 139. Jones PL, Rabinovitch M. Tenascin‐C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circ Res 79: 1131‐1142, 1996.
 140. Karin M, Hunter T. Transcriptional control by protein phosphorylation: Signal transmission from the cell surface to the nucleus. Curr Biol 5(7): 747‐757, 1995.
 141. Kido M, Du L, Sullivan CC, Deutsch R, Jamieson SW, Thistlethwaite PA. Gene transfer of a TIE2 receptor antagonist prevents pulmonary hypertension in rodents. J Thorac Cardiovasc Surg 129: 268‐276, 2005.
 142. Kim KT, Choi HH, Steinmetz MO, Maco B, Kammerer RA, Ahn SY, Kim HZ, Lee GM, Koh GY. Oligomerization and multimerization are critical for angiopoietin‐1 to bind and phosphorylate Tie2. J Biol Chem 280: 20126‐20131, 2005.
 143. Kim S, Ip HS, Lu MM, Clendenin C, Parmacek MS. A serum response factor‐dependent transcriptional regulatory program identifies distinct smooth muscle cell sublineages. Mol Cell Biol 17: 2266‐2278, 1997.
 144. Klein M, Schermuly RT, Ellinghaus P, Milting H, Riedl B, Nikolova S, Pullamsetti SS, Weissmann N, Dony E, Savai R, Ghofrani HA, Grimminger F, Busch AE, Schäfer S. Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling. Circulation 118(20): 2081‐2090, 2008.
 145. Kluck RM, Bossy‐Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: A primary site for Bcl‐2 regulation of apoptosis. Science 275: 1132‐1136, 1997.
 146. Kobs RW, Muvarak NE, Eickhoff JC, Chesler NC. Linked mechanical and biological aspects of remodeling in mouse pulmonary arteries with hypoxia‐induced hypertension. Am J Physiol Heart Circ Physiol 288: H1209‐H1217, 2005.
 147. Komuro I, Kurihara H, Sugiyama T, Yoshizumi M, Takaku F, Yazaki Y. Endothelin stimulates c‐fos and c‐myc expression and proliferation of vascular smooth muscle cells. FEBS Lett 238: 249‐252, 1998.
 148. Kornberg L, Earp HS, Parsons JT, Schaller M, Juliano RL. Cell adhesion or integrin clustering increases phosphorylation of a focal adhesion‐associated tyrosine kinase. J Biol Chem 267: 23439‐23442, 1992.
 149. Kourembanas S, Bernfield M. Hypoxia and endothelial‐smooth muscle cell interactions in the lung. Am J Respir Cell Mol Biol 11: 373‐374, 1994.
 150. Koyama H, Raines EW, Bornfeldt KE, Roberts JM, Ross R. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. Cell 87: 1069‐1078, 1996.
 151. Koyama N, Kinsella MG, Wight TN, Hedin U, Clowes AW. Heparan sulfate proteoglycans mediate a potent inhibitory signal for migration of vascular smooth muscle cells. Circ Res 83: 305‐313, 1998.
 152. Krick S, Platoshyn O, Sweeney M, Kim H, Yuan JXJ. Activation of K+ channels induces apoptosis in vascular smooth muscle cells. Am J Physiol Cell Physiol 280: C970‐C979, 2001.
 153. Krug LM, Berk BC. Na+,K+‐adenosine triphosphatase regulation in hypertrophied vascular smooth muscle cells. Hypertension 20: 144‐150, 1992.
 154. Lagna G, Nguyen PH, Ni W, Hata A. BMP‐dependent activation of caspase‐9 and caspase‐8 mediates apoptosis in pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 291: L1059‐L1067, 2006. doi:10.1152/ajplung.00180.2006.
 155. Lanner MC, Raper M, Pratt WM, Rhoades RA. Heterotrimeric G proteins and the platelet‐derived growth factor receptor‐γ contribute to hypoxic proliferation of smooth muscle cells. Am J Respir Cell Mol Biol 33: 412‐419, 2005.
 156. Launay JM, Herve P, Peoc'h K, Tournois C, Callebert J, Nebigil CG, Etienne N, Drouet L, Humbert M, Simonneau G, Maroteaux L. Function of the serotonin 5‐hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med 8: 1129‐1135, 2002.
 157. Law RE, Goetze S, Xi XP, Jackson S, Kawano Y, Demer L, Fishbein MC, Meehan WP, Hsueh WA. Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation 101: 1311‐18, 2000.
 158. Law RE, Meehan WP, Xi XP, Graf K, Wuthrich DA, Coats W, Faxon D, Hsueh WA. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J Clin Invest 98: 1897‐1905, 1996.
 159. Lawrie A, Spiekerkoetter E, Martinez EC, Ambratsumiam N, Sheward WJ, MacLean MR, Harmar AJ, Schmidt AM, Lukanidin E, Rabinovitch M. Interdependent serotonin transporter and receptor pathways regulate S100A4/Mts1, a gene associated with pulmonary vascular disease. Circ Res 97(3): 227‐235, 2005.
 160. Le Cras TD, McMurtry IF. Nitric oxide production in the hypoxic lung. Am J Physiol Lung Cell Mol Physiol 280: L575‐L582, 2001.
 161. Lee SL, Wang WW, Fanburg BL. Association of Tyr phosphorylation of GTPase‐activating protein with mitogenic action of serotonin. Am J Physiol 272: C223‐C230, 1997.
 162. Lee SL, Wang WW, Fanburg BL. Superoxide as an intermediate signal for serotonin‐induced mitogenesis. Free Radical Biol Med 24: 855‐858, 1998.
 163. Lee SL, Wang WW, Finlay GA, Fanburg BL. Serotonin stimulates mitogen‐activated protein kinase activity through the formation of superoxide anion. Am J Physiol 277: L282‐L291, 1999.
 164. Lee SL, Wang WW, Moore BJ, Fanburg BL. Dual effect of serotonin on growth of bovine pulmonary artery smooth muscle cells in culture. Circ Res 68(5): 1362‐1368, 1991.
 165. Lehmann JM, Moore LB, Smith‐Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator‐activated receptor gamma (PPAR gamma). J Biol Chem 270: 12953‐12956, 1995.
 166. Lehoux S, Esposito B, Merval R, Tedgui A. Differential regulation of vascular focal adhesion kinase by steady stretch and pulsatility. Circulation 111: 643‐649, 2005.
 167. Leitschuh M, Chobanian AV. Inhibition of nuclear polyploidy by propranolol in aortic smooth muscle cells of hypertensive rats. Hypertension 9(Suppl III): III‐106‐III‐109, 1987.
 168. Lepetit H, Eddahibi S, Fadel E, Frisdal E, Munaut C, Noel A, Humbert M, Adnot S, D'Ortho MP, Lafuma C. Smooth muscle cell matrix metalloproteinases in idiopathic pulmonary arterial hypertension. Eur Respir J 25(5): 834‐842, 2005.
 169. Lesprit P, Godeau B, Authier FJ, Soubrier M, Zuber M, Larroche C, Viard JP, Wechsler B, Gherardi R. Pulmonary hypertension in POEMS syndrome: A new feature mediated by cytokines. Am J Respir Crit Care Med 157(3, Pt 1): 907‐911, 1998.
 170. Li C, Wernig F, Leitges M, Hu Y, Xu Q. Mechanical stress‐activated PKCdelta regulates smooth muscle cell migration. FASEB J. 17: 2106‐2108, 2003.
 171. Li DY, Brooke B, Davis EC, Mecham RP, Sorensen LK, Boak BB, Eichwald E, Keating MT. Elastin is an essential determinant of arterial morphogenesis. Nature 393: 276‐280, 1998.
 172. Li L, Miano JM, Cserjesi P, Olson EN. SM22 alpha, a marker of adult smooth muscle, is expressed in multiple myogenic lineages during embryogenesis. Circ Res 78: 188‐195, 1996.
 173. Lim S, Jin CJ, Kim M, Chung SS, Park HS, Lee IK, Lee CT, Cho YM, Lee HK, Park KS. PPARgamma gene transfer sustains apoptosis, inhibits vascular smooth muscle cell proliferation, and reduces neointima formation after balloon injury in rats. Arterioscler Thromb Vasc Biol 26: 808‐813, 2006.
 174. Lin MJ, Leung GP, Zhang WM, Yang XR, Yip KP, Tse CM, Sham JS. Chronic hypoxia‐induced upregulation of store‐operated and receptor operated Ca2+ channels in pulmonary arterial smooth muscle cells: A novel mechanism of hypoxic pulmonary hypertension. Circ Res 95: 496‐505, 2004.
 175. Liu Y, Li M, Warburton R, Hill NS, Fanburg BL. The 5‐HT transporter transactivates the PDGFβ receptor in pulmonary artery smooth muscle cells. FASEB J 21(11): 2725‐2734, 2007.
 176. Liu Y, Wei L, Laskin DL, Fanburg BL. Role of protein transamidation in serotonin‐induced proliferation and migration of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol 2010 [Epub ahead of print].
 177. Lovdahl C, Thyberg J, Hultgardh‐Nilsson A. The synthetic metalloproteinase inhibitor batimastat suppresses injury induced phosphorylation of MAP kinase ERK1/ERK2 and phenotypic modification of arterial smooth muscle cells in vitro. J Vasc Res 37: 345‐354, 2000.
 178. Lu SY, Wang DS, Zhu MZ, Zhang QH, Hu YZ, Pei JM. Inhibition of hypoxia‐induced proliferation and collagen synthesis by vasonatrin peptide in cultured rat pulmonary artery smooth muscle cells. Life Sci 77: 28‐38, 2005.
 179. Mack CP, Owens GK. Regulation of SM alpha‐actin expression in vivo is dependent upon CArG elements within the 5′ and first intron promoter regions. Circ Res 84: 852‐861, 1999.
 180. Madsen CS, Regan CP, Hungerford JE, White SL, Manabe I, Owens GK. Smooth muscle‐specific expression of the smooth muscle myosin heavy chain gene in transgenic mice requires 5′‐ flanking and first intronic DNA sequence. Circ Res 82: 908‐917, 1998.
 181. Maeno E, Ishizaki Y, Kanaseki T, Hazama A, Okada Y. Normotonic cell shrinkage because of disordered volume regulation is an early prerequisite to apoptosis. Proc Natl Acad Sci USA 97(17): 9487‐92, 2000.
 182. Mandegara M, Fung YC, Huang W, Remillard CV, Rubina LJ, Yuana JX. Cellular and molecular mechanisms of pulmonary vascular remodeling: Role in development of pulmonary hypertension. Microvasc Res 8(2): 75‐103, 2004
 183. Marasini B, Cossutta R, Selmi C, Pozzi MR, Gardinali M, Massarotti M, Erario M, Battaglioli L, Biondi ML. Polymorphism of the fractalkine receptor CX3CR1 and systemic sclerosis‐associated pulmonary arterial hypertension. Clin Dev Immunol 12(4): 275‐279, 2005.
 184. Marcos E, Fadel E, Sanchez O, Humbert M, Dartevelle P, Simonneau G, Hamon M, Adnot S, Eddahibi S. Serotonin‐induced smooth muscle hyperplasia in various forms of human pulmonary hypertension. Circ Res 94(9): 1263‐70, 2004.
 185. Marx N, Schonbeck U, Lazar MA, Libby P, Plutzky J. Peroxisome proliferator‐activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res 83: 1097‐1103, 1998.
 186. Marx NN, Duez HH, Fruchart JCJ‐C, Staels BB. Peroxisome proliferator‐activated receptors and atherogenesis: Regulators of gene expression in vascular cells. Circ Res 94: 1168‐1178, 2004.
 187. Massague J, Chen YG. Controlling TGF‐beta signaling. Genes Dev 14: 627‐644, 2000.
 188. Mauban JR, Remillard CV, Yuan JX. Hypoxic pulmonary vasoconstriction: Role of ion channels. J Appl Physiol 98: 415‐420, 2005.
 189. McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, bonnet S, Puttagunta L, Michelakis ED. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest 115(6): 1479‐1491, 2005.
 190. Merklinger SL, Jones PL, Martinez EC, Rabinovitch M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112(3): 423‐431, 2005.
 191. Meyrick B, Reid L. Hypoxia and incorporation of 3Hthymidine by cells of the rat pulmonary arteries and alveolar wall. Am J Path 96: 51‐70, 1979.
 192. Meyrick B, Reid L. Hypoxia‐induced structural changes in the media and adventitia of the rat hilar pulmonary artery and their regression. Am J Pathol 100(1): 151‐178, 1980.
 193. Miano JM, Carlson MJ, Spencer JA, Misr RP. Serum response factor‐dependent regulation of the smooth muscle calponin gene. J Biol Chem 275: 9814‐9822, 2000.
 194. Miano JM, Cserjesi P, Ligon K, Perisamy M, Olson EN. Smooth muscle myosin heavy chain marks exclusively the smooth muscle lineage during mouse embryogenesis. Circ Res 75: 803‐812, 1994.
 195. Miano JM, Olson EN. Expression of the smooth muscle cell calponin gene marks the early cardiac and smooth muscle cell lineages during mouse embryogenesis. J Biol Chem 271: 7095‐7103, 1996.
 196. Microfilaments and Intermediate Filaments‐Cell Locomotion. In: Lodish H, Berk A, Kaiser CA, Krieger M, Scott MP, Bretcher A, Ploegh H, Matsudaira P, editors. Molecular Cell Biology. 6th ed. New York: W.H. Freeman & Co, 2008, p. 847‐903.
 197. Mills I, Cohen CR, Kamal K, Li G, Shin T, Du W, Sumpio BE. Strain activation of bovine aortic smooth muscle cell proliferation and alignment: Study of strain dependency and the role of protein kinase A and C signaling pathways. Jour Cell Physiol 170: 228‐34, 1997.
 198. Mogami H, Kojima I. Stimulation of calcium entry is prerequisite for DNA synthesis induced by platelet‐derived growth factor in vascular smooth muscle cells. Biochem Biophys Res Commun 196: 650‐658, 1993.
 199. Morinelli TA, Zhang LM, Newman WH, Meier KE. Thromboxane A2/prostaglandin H2‐stimulated mitogenesis of coronary artery smooth muscle cells involves activation of mitogen‐activated protein kinase and S6 kinase. J Biol Chem 269: 5693‐5698, 1994.
 200. Morrell NW. Pulmonary hypertension due to BMPR2 mutation: A new paradigm for tissue remodelling? Proc Am Thorac Soc 3: 680‐686, 2006.
 201. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, Yuan JX, Weir EK. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol 54(Suppl 1): S20‐S31, 2009.
 202. Morrell NW, Yang X, Upton, PD, Jourdan KB, Morgan N, Sheares KK, Trembath RC. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor‐b1 and bone morphogenetic proteins. Circulation 104: 790‐795, 2001.
 203. Moudgil R, Michelakis ED, Archer SL. Hypoxic pulmonary vasoconstriction. J Appl Physiol 98: 390‐403, 2005.
 204. Nelson MT, Patlak JB, Worley JF, Standen NB. Calcium channels, potassium channels and voltage dependence of arterial smooth muscle tone. Am J Physiol Cell Physiol 259: C3‐C18, 1990.
 205. Nelson MT, Quayle JM. Physiological roles and properties of potassium channels in arterial smooth muscle. Am J Physiol Cell Physiol 268, C799‐C822, 1995.
 206. Nelson PR, Yamamura S, Kent KC. Extracellular matrix proteins are potent agonists of human smooth muscle cell migration. J Vasc Surg 24: 25‐32, 1996.
 207. Newby AC, George SJ. Proliferation, migration, matrix turnover and death of smooth muscle cells in native coronary and vein graft atherosclerosis. Curr Opin Cardiol 11: 574‐582, 1996.
 208. Newton CS, Loukinova E, Mikhailenko I, Ranganathan S, Gao Y, Haudenschild C, Strickland DK. Platelet‐derived growth factor receptor‐beta (PDGFR‐beta) activation promotes its association with the low density lipoprotein receptor‐related protein (LRP): Evidence for co‐receptor function. J Biol Chem 280: 27872‐27878, 2005.
 209. Nicolls MR, Taraseviciene‐Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: A perspective. Eur Respir J 26: 1110‐1118, 2005.
 210. Numaguchi K, Eguchi S, Yamakawa T, Motley ED, Inagami T. Mechanotransduction of rat aortic vascular smooth muscle cells requires RhoA and intact actin filaments. Circ Res 85: 5‐11, 1999.
 211. Ogawa D, Nomiyama T, Nakamachi T, Heywood EB, Stone JF, Berger JP, Law RE, Bruemmer D. Activation of peroxisome proliferator‐activated receptor gamma suppresses telomerase activity in vascular smooth muscle cells. Circ Res 98: e50‐e59, 2006.
 212. Owens GK. Differential effects of antihypertensive drug therapy on vascular smooth muscle cell hypertrophy, hyperploidy and hyperplasia in the spontaneously hypertensive rat. Circ Res 56: 525‐536, 1985.
 213. Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84: 767‐801, 2004.
 214. Pak A, Aldashev A, Welsh D. The effects of hypoxia on the cells of the pulmonary vasculature. Eur Respir J 30: 364‐372, 2007.
 215. Parekh AB, Penner R. Store depletion and calcium influx. Physiol Rev 77: 901‐930, 1997.
 216. Parks WC, Mecham RP, Crouch EC, Orton EC, Stenmark KR. Response of lobar vessels to hypoxic pulmonary hypertension. Am Rev Respir Dis 140: 1455‐1457, 1989.
 217. Perros F, Dorfmuller P, Souza R, Durand‐Gasselin I, Godot V, Capel F, Adnot S, Eddahibi S, Mazmanian M, Fadel E, Hervé P, Simonneau G, Emilie D, Humbert M. Fractalkine‐induced smooth muscle cell proliferation in pulmonary hypertension. Eur Respir J 29(5): 937‐943, 2007.
 218. Perros F, Montani D, Dorfmüller P, Durand‐Gasselin I, Tcherakian C, Le Pavec J, Mazmanian M, Fadel E, Mussot S, Mercier O, Hervé P, Emilie D, Eddahibi S, Simonneau G, Souza R, Humbert M. Platelet‐derived growth factor expression and function in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 178(1): 81‐88, 2008.
 219. Petkov V, Mosgoeller W, Ziesche R, Raderer M, Stiebellehner L, Vonbank K, Funk GC, Hamilton G, Novotny C, Burian B, Block LH. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 111: 1339‐1346, 2003.
 220. Peyton SR, Putnam AJ. Extracellular matrix rigidity governs smooth muscle cell motility in a biphasic fashion. J Cell Physiol 204: 198‐209, 2005.
 221. Pitt BR, Weng WL, Steve AR, Blakely RD, Reynolds I, Davies P. Serotonin increases DNA synthesis in rat proximal and distal pulmonary vascular smooth muscle cells in culture. Am J Physiol 266(2): L178‐L186, 1994.
 222. Platoshyn O, Golovina VA, Bailey CL, Limsuwan A, Krick S, Juhaszova M, Seiden JE, Rubin LJ, Yuan JX. Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation. Am J Physiol Cell Physiol 279: C1540‐C1549, 2000.
 223. Potgens AJ, Westphal HR, de Waal RM, Ruiter DJ. The role of vascular permeability factor and basic fibroblast growth factor in tumor angiogenesis. Biol Chem Hoppe Seyler 376: 57‐70, 1995.
 224. Preston IR, Hill NS, Warburton RR, Fanburg BL. Role of 12‐lipoxygenase in hypoxia‐induced rat pulmonary artery smooth muscle cell proliferation. Am J Physiol Lung Cell Mol Physiol 290: L367‐L374, 2006.
 225. Prins BA, Hu R‐M, Nazario B, Frank HJ, Weber MA, Levin ER. Prostaglandin E2 and prostacyclin inhibit the production and secretion of endothelin from cultured aortic endothelial cells. J Biol Chem 269: 11938‐119344, 1994.
 226. Prosser IW, Stenmark KR, Suthar M, Crouch EC, Mecham RP, Parks WC. Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonary hypertension as demonstrated by in situ hybridization. Am J Pathol 135(6): 1073‐1088, 1989.
 227. Quinn TP, Schlueter M, Soifer SJ, Gutierrez JA. Cyclic mechanical stretch induces VEGF and FGF‐2 expression in pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 282(5): L897‐L903, 2002.
 228. Rabinovitch M. Elastase and the pathobiology of the unexplained pulmonary hypertension. Chest 114(3)(Suppl): 213S‐224S, 1998.
 229. Rabinovitch M. Pathobiology of pulmonary hypertension. Annu Rev Pathol Mech Dis 2: 369‐399, 2007.
 230. Rabinovitch M, Bothwell T, Hayakawa BN, Williams WG, Trusler GA, Rowe RD, Olley PM, Cutz E. Pulmonary artery endothelial abnormalities in patients with congenital heart disease and pulmonary hypertension: A correlation of light with scanning electron microscopy and transmission electron microscopy. Lab Invest 55: 632‐653, 1986.
 231. Rabinovitch M, Gamble W, Nadas AS, Miettinen OS, Reid L. Rat pulmonary circulation after chronic hypoxia: Hemodynamic and structural features. Am J Physiol 236: H818‐H827, 1979.
 232. Regulating the eukaryotic cell cycle. In: Lodish H, Berk A, Kaiser CA, Krieger M, Scott MP, Bretcher A, Ploegh H, Matsudaira P, editors. Molecular Cell Biology. 6th ed. New York: W.H. Freeman & Co, 2008, p. 847‐903.
 233. Remillard CV, Yuan JX. High altitude pulmonary hypertension: Role of K+ and Ca2+ channels. High Alt Med Biol 6: 133‐146, 2005.
 234. Ross S, Hill C. How the Smads regulate transcription. Int J Biochem Cell Biol 40(3): 383‐403, 2008.
 235. Sage EH, Bornstein P. Extracellular proteins that modulate cell‐matrix interactions. SPARC, tenascin, and thrombospondin. J. Biol. Chem. 1991; 266: 14831‐14834.
 236. Said S. Mediators and modulators of pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 291: L547‐L558, 2006.
 237. Sanchez O, Marcos E, Perros F, Fadel E, Tu L, Humbert M, Dartevelle P, Simonneau G, Adnot S, Eddahibi S. Role of endothelium‐derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 176(10): 1041‐1047, 2007.
 238. Sartore S, Chiavegato A, Faggin E, Franch R, Puato M, Ausoni S, Pauletto P. Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: From innocent bystander to active participant. Circ Res 89: 1111‐1121, 2001.
 239. Sato Y, Hamanaka R, Ono J, Kuwano M, Rifkin DB, Takaki R. The stimulatory effect of PDGF on vascular smooth muscle cell migration is mediated by the induction of endogenous basic FGF. Biochem Biophys Res Commun 174: 1260‐1266, 1991.
 240. Savale L, Tu L, Rideau D, Izziki M, Maitre B, Adnot S, Eddahibi S. Impact of interleukin‐6 on hypoxia‐induced pulmonary hypertension and lung inflammation in mice. Respir Res 10: 6, 2009.
 241. Scala E, Pallotta S, Frezzolini A, Abeni D, Barbieri C, Sampogna F, De Pita O, Puddu P, Paganelli R, Russo G. Cytokine and chemokine levels in systemic sclerosis: Relationship with cutaneous and internal organ involvement. Clin Exp Immunol 138(3): 540‐546, 2004.
 242. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest 115(10): 2811‐2821, 2005.
 243. Schlaepfer DD, Hunter T. Focal adhesion kinase overexpression enhances ras‐dependent integrin signaling to ERK2/mitogen‐activated protein kinase through interactions with and activation of c‐Src. J Biol Chem 272: 13189‐13195, 1997.
 244. Schmierer B, Hill C. TGFβ‐Smad signal transduction: Molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8: 970‐982, 2007.
 245. Schober A, Zernecke A. Chemokines in vascular remodeling. Thromb Haemost 97(5): 730‐737, 2007.
 246. Schultz K, Fanburg BL, Beasley B. Hypoxia and hypoxia‐inducible factor‐1alpha promote growth factor‐induced proliferation of human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 290: 2528‐2534, 2006.
 247. Scott NA, Cipolla GD, Ross CE, Dunn B, Martin FH, Simonet L, Wilcox JN. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation 93(12): 2178‐2187, 1996.
 248. Seay U, Sedding D, Krick S, Hecker M, Seeger W, Eickelberg O. TGF‐β‐dependent growth inhibition in primary vascular smooth muscle cells is p38‐dependent. J Pharmacol Exp Ther 315: 1005‐1012, 2005.
 249. Semenza GL. Oxygen‐regulated transcription factors and their role in pulmonary disease. Respir Res 1: 159‐162, 2000.
 250. Sherr CJ, Roberts JM. CDK inhibitors: Positive and negative regulators of G1‐phase progression. Genes Dev 13: 1501‐1512, 1999.
 251. Shi Y, Massague J. Mechanisms of TGF‐beta signaling from cell membrane to nucleus. Cell 113: 685‐700, 2003.
 252. Shi Y, O'Brien JE, Fard A, Mannion JD, Wang D, Zalewski A. Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation 94(7): 1655‐1664, 1996.
 253. Shimoda LA, Sylvester JT, Sham JS. Chronic hypoxia alters effects of endothelin and angiotensin on K+ currents in pulmonary arterial myocytes. Am J Physiol 277(3 pt 1): L431‐L439, 1999.
 254. Skalli O, Ropraz P, Trzeciak A, Benzonana G, Gillessen D, Gabbiani G. A monoclonal antibody against α‐smooth muscle actin: A new probe for smooth muscle differentiation. J Cell Biol 103: 2787‐2796, 1986.
 255. Southgate KM, Davies M, Booth RF, Newby AC. Involvement of extracellular‐matrix‐degrading metalloproteinases in rabbit aortic smooth‐muscle cell proliferation. Biochem J 288: 93‐99, 1992.
 256. Spivak‐Kroizman T, Lemmon MA, Dikic I, Ladbury JE, Pinchasi D, Huang J, Jaye M, Crumley G, Schlessinger J, Lax I. Heparinin induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation. Cell 79: 1015‐1024, 1994.
 257. Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Interleukin‐6 overexpression induces pulmonary hypertension. Circ Res 104(2): 236‐244, 2008.
 258. Stenmark KR, Fagan KA, Frid, MG. Hypoxia‐induced pulmonary vascular remodeling: Cellular and molecular mechanisms. Circ Res 99: 675‐691, 2006.
 259. Stevens T, Phan S, Frid MG, Alvarez D, Herzog E, Stenmark KR. Lung vascular cell heterogeneity: Endothelium, smooth muscle, and fibroblasts. Proc Am Thorac Soc 5(7): 783‐791, 2008.
 260. Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin‐1 in pulmonary hypertension: Marker or mediator of disease? Ann Intern Med 114: 464‐469, 1991.
 261. Stiebellehner L, Frid M, Reeves J, Low RB, Gnanasekharan M, Stenmark KR. Bovine distal pulmonary arterial media is composed of a uniform population of well‐differentiated smooth muscle cells with low proliferative capabilities. Am J Physiol Lung Cell Mol Physiol 285: L819‐L828, 2003.
 262. Stotz W, Li D, Johns RA. Exogenous nitric oxide upregulates p21waf1/cip1 in pulmonary microvascular smooth muscle cells. J Vasc Res 41: 211‐219, 2004.
 263. Strasser P, Gimona M, Moessler H, Herzog M, Small JV. Mammalian calponin: Identification and expression of genetic variants. FEBS Lett 330: 13‐18, 1993.
 264. Sullivan CC, Du L, Chu D, Cho AJ, Kido M, Wolf PL, Jamieson SW, Thistlethwaite PA. Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. Proc Natl Acad Sci USA 100: 12331‐12336, 2003.
 265. Sumpio BE, Banes AJ. Response of porcine aortic smooth muscle cells to cyclic tensional deformation in culture. J Surg Res 44: 696‐701, 1988.
 266. Taipale J, Keski‐Oja J. Growth factors in the extracellular matrix. FASEB J 11: 51‐59, 1997.
 267. Tamm M, Bihl M, Eickelberg O, Stulz P, Peruchoud AP, Roth M. Hypoxia‐induced interleukin‐6 and interleukin‐8 production is mediated by platelet‐activating factor and platelet‐derived growth factor in primary human lung cells. Am J Respir Cell Mol Biol 19: 653‐661, 1998.
 268. Tedgui A, Mallat Z. Cytokines in atherosclerosis: Pathogenic and regulatory pathways. Physiol Rev 86(2): 515‐581, 2006.
 269. The cell cycle. In: Cooper GM, Hausman RE, editors. The Cell: A Molecular Approach. 3rd ed. Sunderland, MA: Sinauer Associates Inc, 2004, p. 591‐630.
 270. Thistlethwaite PA, Lee SH, Du LL, Wolf PL, Sullivan C, Pradhan S, Deutsch R, Jamieson SW. Human angiopoietin gene expression is a marker for severity of pulmonary hypertension in patients undergoing pulmonary thromboendarterectomy. J Thorac Cardiovasc Surg 122: 65‐73, 2001.
 271. Thompson K, Rabinovitch M. Exogenous leukocyte and endogenous elastases can mediate mitogenic activity in pulmonary artery smooth muscle cells by release of extracellular matrix bound basic fibroblast growth factor. J Cell Physiol 166: 495‐505, 1996.
 272. Thomson JR, Machado RD, Pauciulo MW, Morgan NV, Humbert M, Elliott GC, Ward K, Yacoub M, Mikhail G, Rogers P, Newman J, Wheeler L, Higenbottam T, Gibbs JS, Egan J, Crozier A, Peacock A, Allcock R, Corris P, Loyd JE, Trembath RC, Nichols WC. Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR‐II, a receptor member of the TGF‐beta family. J Med Genet 37: 741‐745, 2000.
 273. Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science 281: 1312‐1316, 1998.
 274. Todorovich‐Hunter L, Dodo H, Ye C, McCready L, Keeley FW, Rabinovitch M. Increased pulmonary artery elastolytic activity in adult rats with monocrotaline‐induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. Am Rev Respir Dis 1992; 146: 213‐23.
 275. Todorovich‐Hunter L, Johnson DJ, Ranger P, Keeley FW, Rabinovitch M. Altered elastin and collagen synthesis associated with progressive pulmonary hypertension induced by monocrotaline: A biochemical and ultrastructural study. Lab Invest 1988; 58: 184‐195.
 276. Trembath RC, Thomson JR, Machado RD, Morgan NV, Atkinson C, Winship I, Simonneau G, Galie N, Loyd JE, Humbert M, Nichols WC, Morrell NW, Berg J, Manes A, McGaughran J, Pauciulo M, Wheeler L. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 345: 325‐334, 2001.
 277. Tseng H, Berk BC. The Na/K/2Cl cotransporter is increased in hypertrophied vascular smooth muscle cells. J Biol Chem 267: 8161‐8167, 1992.
 278. Tuder RM, Cool CD, Geraci MW, Wang J, Abman SH, Wright L, Badesch D, Voelkel NF. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 159: 1925‐1932, 1999.
 279. Ushio‐Fukai M, Griedling KK, Becker PL, Hilenski L, Halleran S, Alexander RW. Epidermal growth factor receptor transactivation by angiotensin II requires reactive oxygen species in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 21: 489‐495, 2001.
 280. Van Der Loop FTL, Schaart G, Timmer EDJ, Ramaekers FCS, van Eys GJJM. Smoothelian, a novel cytoskeletal protein specific for smooth muscle cells. J Cell Biol 134: 401‐411, 1996.
 281. Vieillard‐Baron A, Frisdal E, Eddahibi S, Deprez I, Baker AH, Newby AC, Berger P, Levame M, Raffestin B, Adnot S, d'Ortho MP. Inhibition of matrix metalloproteinases by lung TIMP‐1 gene transfer or doxycycline aggravates pulmonary hypertension in rats. Circ Res 87: 418‐425, 2000.
 282. Vieillard‐Baron A, Frisdal E, Raffestin B, Baker AH, Eddahibi S, Adnot S, D'Ortho MP. Inhibition of matrix metalloproteinases by lung TIMP‐1 gene transfer limits monocrotaline‐induced pulmonary vascular remodelling in rats. Hum Gene Ther 14: 861‐869, 2003.
 283. Vu CC, Bortner CD, Cidlowski JA. Differential involvement of initiator caspases in apoptotic volume decrease and potassium efflux during Fas‐ and UV‐induced cell death. J Biol Chem 276: 37602‐37611, 2001.
 284. Wakino S, Kintscher U, Kim S, Yin F, Hsueh WA, Law RE. Peroxisome proliferator‐activated receptor gamma ligands inhibit retinoblastoma phosphorylation and G1‐S transition in vascular smooth muscle cells. J Biol Chem 275: 22435‐41, 2000.
 285. Wang J, Weigand L, Wang W, Sylvester JT, Shimoda LA. Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery. Am J Physiol Lung Cell Mol Physiol 288: L1049‐L1058, 2005.
 286. Wang Z, Newman WH. Smooth muscle cell migration stimulated by interleukin 6 is associated with cytoskeletal reorganization. J Surg Res 111: 261‐266, 2003.
 287. Ward MR, Tsao PS, Agrotis A, Dilley RJ, Jennings GL, Bobik A. Low blood flow after angioplasty augments mechanisms of restenosis: Inward vessel remodeling, cell migration, and activity of genes regulating migration. Arterioscler Thromb Vasc Biol. 21: 208‐213, 2001.
 288. Weiser MC, Majack RA, Tucker A, Orton EC. Static tension is associated with increased smooth muscle cell DNA synthesis in rat pulmonary arteries. Am J Physiol 268(3 Pt 2): H1133‐H1138, 1995.
 289. Wharton J, Davie N, Upton PD, Yacoub MH, Polak JM, Morrell NW. Prostacyclin analogues differentially inhibit growth of distal and proximal human pulmonary artery smooth muscle cells. Circulation 102: 3130‐3136, 2000.
 290. Wilson E, Mai Q, Sudhir K, Weiss RH, Ives HE. Mechanical strain induces growth of vascular smooth muscle cells via autocrine action of PDGF. Tour Cell Biol 123: 741‐747, 1993.
 291. Wohrley JD, Frid MG, Moiseeva EP, Orton EC, Belknap JK, Stenmark KR. Hypoxia selectively induces proliferation in a specific subpopulation of smooth muscle cells in the bovine neonatal pulmonary arterial media. J Clin Invest 96: 273‐281, 1995.
 292. Yabkowitz R, Mansfield PJ, Ryan US, Suchard SJ. Thrombospondin mediates migration and potentiates platelet‐derived growth factor‐dependent migration of calf pulmonary artery smooth muscle cells. J Cell Physiol 157: 24‐32, 1993.
 293. Yanagisawa M. The endothelin system: A new target for therapeutic intervention. Circulation 89: 1320‐1322, 1994.
 294. Yang X, Long L, Southwood M, Rudarakanchana N, Upton PD, Jeffery TK, Atkinson C, Chen H, Trembath RC, Morrell NW. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 96(10): 1053‐63, 2005.
 295. Ye C, Rabinovitch M. Inhibition of elastolysis by SC‐37698 reduces development and progression of monocrotaline pulmonary hypertension. Am J Physiol 1991; 261: H1255‐H1267.
 296. Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM. Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res 88(1): E2‐E11, 2001.
 297. Yoshio T, Masuyama JI, Kohda N, Hirata D, Sato H, Iwamoto M, Mimori A, Takeda A, Minota S, Kano S. Association of interleukin 6 release from endothelial cells and pulmonary hypertension in SLE. J Rheumatol 24(3): 489‐495, 1997.
 298. Young KA, Ivester C, West J, Carr M, Rodman DM. BMP signaling controls PASMC KV channel expression in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 290(5): L841‐L848, 2006.
 299. Yu PB, Deng DY, Beppu H, Hong CC, Lai C, Hoyng SA, Kawai N, Bloch KD. Bone morphogenetic protein (BMP) type II receptor is required for BMP‐mediated growth arrest and differentiation in pulmonary artery smooth muscle cells. J Biol Chem 283(7): 3877‐3888, 2008.
 300. Yu Y, Fantozzi I, Remillard CV, Landsberg JW, Kunichika N, Platoshyn O, Tigno DD, Thistlethwaite PA, Rubin LJ, Yuan JX. Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc Natl Acad Sci USA 2004; 101(38): 13861‐13866.
 301. Yu Y, Sweeney M, Zhang S, Platoshyn O, landsberg J, Rothman A, Yuan JX. PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. Am J Physiol Cell Physiol 284: C316‐C330, 2003.
 302. Yuan JX, Aldinger AM, Juhaszova M, Wang J, Conte JV Jr, Gaine SP, Orens JB, Rubin LJ. Dysfunctional voltage gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 98: 1400‐1406, 1998.
 303. Yuan JX, Wang J, Juhaszova M, Gaine SP, Rubin LJ. Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet 351: 726‐727, 1998.
 304. Zhang J, Fu M, Zhao L, Chen YE. 15‐Deoxy‐prostaglandin J(2) inhibits PDGF‐A and ‐B chain expression in human vascular endothelial cells independent of PPAR gamma. Biochem Biophys Res Commun 298: 128‐132, 2002.
 305. Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA, Kriett JM, Yung G, Rubin LJ, Yuan JX. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285: L740‐L754, 2003.
 306. Zhao YD, Campbell AI, Robb M, Ng D, Stewart DJ. Protective role of angiopoietin‐1 in experimental pulmonary hypertension. Circ Res 92: 984‐991, 2003.
Cross‐References:
 1. Pulmonary vascular diseases
 2. Regulation of pulmonary vascular smooth muscle cell phenotype and matrix protein synthesis
 3. Adventitial fibrocytes, fibroblasts, and myofibroblasts in pulmonary hypertension
 4. Genetics of pulmonary hypertension
 5. Endothelial and smooth muscle cell ion channels in pulmonary vasoconstriction and vascular remodeling

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Article Title: Smooth Muscle Cell Hypertrophy, Proliferation, Migration and Apoptosis in Pulmonary Hypertension
 

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Tamara Tajsic, Nicholas W. Morrell. Smooth Muscle Cell Hypertrophy, Proliferation, Migration and Apoptosis in Pulmonary Hypertension. Compr Physiol 2010, 1: 295-317. doi: 10.1002/cphy.c100026