Comprehensive Physiology Wiley Online Library

The Adventitia: Essential Role in Pulmonary Vascular Remodeling

Full Article on Wiley Online Library



Abstract

A rapidly emerging concept is that the vascular adventitia acts as a biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. It is the most complex compartment of the vessel wall and comprises a variety of cells including fibroblasts, immunomodulatory cells, resident progenitor cells, vasa vasorum endothelial cells, and adrenergic nerves. In response to vascular stress or injury, resident adventitial cells are often the first to be activated and reprogrammed to then influence tone and structure of the vessel wall. Experimental data indicate that the adventitial fibroblast, the most abundant cellular constituent of adventitia, is a critical regulator of vascular wall function. In response to vascular stresses such as overdistension, hypoxia, or infection, the adventitial fibroblast is activated and undergoes phenotypic changes that include proliferation, differentiation, and production of extracellular matrix proteins and adhesion molecules, release of reactive oxygen species, chemokines, cytokines, growth factors, and metalloproteinases that, collectively, affect medial smooth muscle cell tone and growth directly and that stimulate recruitment and retention of circulating inflammatory and progenitor cells to the vessel wall. Resident dendritic cells also participate in “sensing” vascular stress and actively communicate with fibroblasts and progenitor cells to simulate repair processes that involve expansion of the vasa vasorum, which acts as a conduit for further delivery of inflammatory/progenitor cells. This review presents the current evidence demonstrating that the adventitia acts as a key regulator of pulmonary vascular wall function and structure from the “outside in.” © 2011 American Physiological Society. Compr Physiol 1:141‐161, 2011.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

Complex cellular composition of the vascular adventitia. Unlike the normal intima and media, which are composed of endothelial and smooth muscle cells, respectively, the normal adventitia comprises a wide variety of cell types, including fibroblasts, resident progenitor cells, immunomodulatory cells (dendritic cells, macrophages, T lymphocytes), vasa vasorum endothelial cells, and adrenergic nerves.

Figure 2. Figure 2.

Fibroblasts play a central role in the control of vascular function. Fibroblasts produce and organize elements of extracellular matrix (ECM) and also degrade structural elements of the ECM; they secrete a complex mixture of growth factors, cytokines, chemokines; they communicate with neural cells with cells of hematopoietic origin (dendritic cells, macrophages, T lymphocytes), with SMCs and endothelial and epithelial cells; importantly, this communication is reciprocal. Abbreviations: MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix metalloproteinases. Adapted from reference .

Figure 3. Figure 3.

Multiple origins for myofibroblasts in the vasculature: α‐SM‐actin‐expressing myofibroblasts are believed to originate via: (i) differentiation of tissue resident fibroblasts, (ii) de‐differentiation of resident smooth muscle cell (SMC), (iii) epithelial‐to‐mesenchymal transdifferentiation (EMT), (iv) endothelial‐to‐mesenchymal transition (EnMT), (v) differentiation of resident or bone marrow‐derived circulating progenitor cells.

.

Adapted from Hinz B, et al. The myofibroblast: one function, multiple origins. Am J Pathol 170(6): 1807‐1816, 2007
Figure 4. Figure 4.

Essential role of the adventitial fibroblast in initiating and perpetuating vascular inflammation and, consequently, vascular remodeling. In response to hormonal, infectious, or environmental (hypoxia, hemodynamic stress, etc.) stimuli, the fibroblast is activated and secretes chemokines, cytokines, and matricellular proteins involved in the recruitment of monocytes, lymphocytes, and progenitor cells. With time, fibroblasts upregulate adhesion molecule expression, which promotes retention of leukocytes and progenitor cells within the adventitia. Some of the newly recruited cells can differentiate into fibroblasts and myofibroblasts, which perpetuate the cycle, thus leading to persistent inflammation and structural vascular remodeling. Abbreviation: PA, pulmonary artery.

Figure 5. Figure 5.

(A‐E), Angiogenic expansion of the vasa vasorum in the pulmonary artery adventitia of calves with severe hypoxia‐induced pulmonary hypertension. Histopathology of large (A, C) and small (B, D) pulmonary arteries. Both histological, H&E (A, B) and immunofluorescent, PECAM‐1/CD31 (C, D) stainings demonstrate marked expansion of the vasa vasorum capillary network in adventitial, perivascular regions. Quantitative morphometric analyses demonstrated that the volume density (Vv) of vasa vasorum is significantly greater in neonatal calves with severe hypoxia‐induced pulmonary hypertension compared with normoxic controls (E). (F, G) Angiogenic responses in the adventitia of a human patient with pulmonary fibrosis and associated pulmonary hypertension. Medium sized pulmonary artery stained with CD31, demonstrating evidence for capillary network expansion in the perivascular area (medial/adventitial region, arrow) (F). CD31 immunohistochemical evidence of capillary proliferation (arrow) (G). Bars, 500 μm in A and C, 100 μm in B, D, F, and 25 μm in G.



Figure 1.

Complex cellular composition of the vascular adventitia. Unlike the normal intima and media, which are composed of endothelial and smooth muscle cells, respectively, the normal adventitia comprises a wide variety of cell types, including fibroblasts, resident progenitor cells, immunomodulatory cells (dendritic cells, macrophages, T lymphocytes), vasa vasorum endothelial cells, and adrenergic nerves.



Figure 2.

Fibroblasts play a central role in the control of vascular function. Fibroblasts produce and organize elements of extracellular matrix (ECM) and also degrade structural elements of the ECM; they secrete a complex mixture of growth factors, cytokines, chemokines; they communicate with neural cells with cells of hematopoietic origin (dendritic cells, macrophages, T lymphocytes), with SMCs and endothelial and epithelial cells; importantly, this communication is reciprocal. Abbreviations: MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix metalloproteinases. Adapted from reference .



Figure 3.

Multiple origins for myofibroblasts in the vasculature: α‐SM‐actin‐expressing myofibroblasts are believed to originate via: (i) differentiation of tissue resident fibroblasts, (ii) de‐differentiation of resident smooth muscle cell (SMC), (iii) epithelial‐to‐mesenchymal transdifferentiation (EMT), (iv) endothelial‐to‐mesenchymal transition (EnMT), (v) differentiation of resident or bone marrow‐derived circulating progenitor cells.

.

Adapted from Hinz B, et al. The myofibroblast: one function, multiple origins. Am J Pathol 170(6): 1807‐1816, 2007


Figure 4.

Essential role of the adventitial fibroblast in initiating and perpetuating vascular inflammation and, consequently, vascular remodeling. In response to hormonal, infectious, or environmental (hypoxia, hemodynamic stress, etc.) stimuli, the fibroblast is activated and secretes chemokines, cytokines, and matricellular proteins involved in the recruitment of monocytes, lymphocytes, and progenitor cells. With time, fibroblasts upregulate adhesion molecule expression, which promotes retention of leukocytes and progenitor cells within the adventitia. Some of the newly recruited cells can differentiate into fibroblasts and myofibroblasts, which perpetuate the cycle, thus leading to persistent inflammation and structural vascular remodeling. Abbreviation: PA, pulmonary artery.



Figure 5.

(A‐E), Angiogenic expansion of the vasa vasorum in the pulmonary artery adventitia of calves with severe hypoxia‐induced pulmonary hypertension. Histopathology of large (A, C) and small (B, D) pulmonary arteries. Both histological, H&E (A, B) and immunofluorescent, PECAM‐1/CD31 (C, D) stainings demonstrate marked expansion of the vasa vasorum capillary network in adventitial, perivascular regions. Quantitative morphometric analyses demonstrated that the volume density (Vv) of vasa vasorum is significantly greater in neonatal calves with severe hypoxia‐induced pulmonary hypertension compared with normoxic controls (E). (F, G) Angiogenic responses in the adventitia of a human patient with pulmonary fibrosis and associated pulmonary hypertension. Medium sized pulmonary artery stained with CD31, demonstrating evidence for capillary network expansion in the perivascular area (medial/adventitial region, arrow) (F). CD31 immunohistochemical evidence of capillary proliferation (arrow) (G). Bars, 500 μm in A and C, 100 μm in B, D, F, and 25 μm in G.

References
 1. Acloque H, Adams MS, Fishwick K, Bronner‐Fraser M, Nieto MA. Epithelial‐mesenchymal transitions: the importance of changing cell state in development and disease. J Clin Invest 119: 1438‐1449, 2009.
 2. Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, Vulto I, Xie M, Qi X, Tuder RM, Phillips JA III, Lansdorp PM, Loyd JE, Armanios MY. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci USA 105: 13051‐13056, 2008.
 3. Arciniegas E, Frid MG, Douglas IS, Stenmark KR. Perspectives on endothelial‐to‐mesenchymal transition: | Potential contribution to vascular remodeling in chronic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 293: L1‐L8, 2007.
 4. Ardanaz N, Pagano PJ. Hydrogen peroxide as a paracrine vascular mediator: Regulation and signaling leading to dysfunction. Exp Biol Med (Maywood) 231: 237‐251, 2006.
 5. Arribas SM, Hillier C, Gonzalez C, McGrory S, Dominiczak AF, McGrath JC. Cellular aspects of vascular remodeling in hypertension revealed by confocal microscopy. Hypertension 30: 1455‐1464, 1997.
 6. Azumi H, Inoue N, Takeshita S, Rikitake Y, Kawashima S, Hayashi Y, Itoh H, Yokoyama M. Expression of NADH/NADPH oxidase p22phox in human coronary arteries. Circulation 100: 1494‐1498, 1999.
 7. Banks MF, Gerasimovskaya EV, Tucker DA, Frid MG, Carpenter TC, Stenmark KR. Egr‐1 antisense oligonucleotides inhibit hypoxia‐induced proliferation of pulmonary artery adventitial fibroblasts. J Appl Physiol 98: 732‐738, 2005.
 8. Barger AC, Beeuwkes R III, Lainey LL, Silverman KJ. Hypothesis: Vasa vasorum and neovascularization of human coronary arteries. A possible role in the pathophysiology of atherosclerosis. N Engl J Med 310: 175‐177, 1984.
 9. Barker TH, Hagood JS. Getting a grip on Thy‐1 signaling. Biochim Biophys Acta 1793: 921‐923, 2009.
 10. Barker TH, Pallero MA, MacEwen MW, Tilden SG, Woods A, Murphy‐Ullrich JE, Hagood JS. Thrombospondin‐1‐induced focal adhesion disassembly in fibroblasts requires Thy‐1 surface expression, lipid raft integrity, and Src activation. J Biol Chem 279: 23510‐23516, 2004.
 11. Bayer IM, Caniggia I, Adamson SL, Langille BL. Experimental angiogenesis of arterial vasa vasorum. Cell Tissue Res 307: 303‐313, 2002.
 12. Belknap JK, Orton EC, Ensley B, Tucker A, Stenmark KR. Hypoxia increases bromodeoxyuridine labeling indices in bovine neonatal pulmonary arteries. Am J Respir Cell Mol Biol 16: 366‐371, 1997.
 13. Best PJ, Hasdai D, Sangiorgi G, Schwartz RS, Holmes DR, Jr., Simari RD, Lerman A. Apoptosis. Basic concepts and implications in coronary artery disease. Arterioscler Thromb Vasc Biol 19: 14‐22, 1999.
 14. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature 432: 332‐337, 2004.
 15. Bogatkevich GS, Tourkina E, Abrams CS, Harley RA, Silver RM, Ludwicka‐Bradley A. Contractile activity and smooth muscle alpha‐actin organization in thrombin‐induced human lung myofibroblasts. Am J Physiol Lung Cell Mol Physiol 285: L334‐L343, 2003.
 16. Brauer PR. MMPs—role in cardiovascular development and disease. Front Biosci 11: 447‐478, 2006.
 17. Brooke BS, Karnik SK, Li DY. Extracellular matrix in vascular morphogenesis and disease: Structure versus signal. Trends Cell Biol 13: 51‐56, 2003.
 18. Brouty‐Boye D, Pottin‐Clemenceau C, Doucet C, Jasmin C, Azzarone B. Chemokines and CD40 expression in human fibroblasts. Eur J Immunol 30: 914‐919, 2000.
 19. Buckley CD, Amft N, Bradfield PF, Pilling D, Ross E, Arenzana‐Seisdedos F, Amara A, Curnow SJ, Lord JM, Scheel‐Toellner D, Salmon M. Persistent induction of the chemokine receptor CXCR4 by TGF‐beta 1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J Immunol 165: 3423‐3429, 2000.
 20. Buckley CD, Pilling D, Lord JM, Akbar AN, Scheel‐Toellner D, Salmon M. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol 22: 199‐204, 2001.
 21. Burke DL, Frid MG, Kunrath CL, Karoor V, Anwar A, Wagner BD, Strassheim D, Stenmark KR. Sustained hypoxia promotes the development of a pulmonary artery‐specific chronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol 297: L238‐250, 2009.
 22. Capers Qt, Alexander RW, Lou P, De Leon H, Wilcox JN, Ishizaka N, Howard AB, Taylor WR. Monocyte chemoattractant protein‐1 expression in aortic tissues of hypertensive rats. Hypertension 30: 1397‐1402, 1997.
 23. Caplice NM, Bunch TJ, Stalboerger PG, Wang S, Simper D, Miller DV, Russell SJ, Litzow MR, Edwards WD. Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proc Natl Acad Sci USA 100: 4754‐4759, 2003.
 24. Chambers RC, Leoni P, Kaminski N, Laurent GJ, Heller RA. Global expression profiling of fibroblast responses to transforming growth factor‐beta1 reveals the induction of inhibitor of differentiation‐1 and provides evidence of smooth muscle cell phenotypic switching. Am J Pathol 162: 533‐546, 2003.
 25. Chang HY, Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, Brown PO. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci USA 99: 12877‐12882, 2002.
 26. Chazova I, Loyd JE, Zhdanov VS, Newman JH, Belenkov Y, Meyrick B. Pulmonary artery adventitial changes and venous involvement in primary pulmonary hypertension. Am J Pathol 146: 389‐397, 1995.
 27. Conrad PW, Conforti L, Kobayashi S, Beitner‐Johnson D, Rust RT, Yuan Y, Kim HW, Kim RH, Seta K, Millhorn DE. The molecular basis of O2‐sensing and hypoxia tolerance in pheochromocytoma cells. Comp Biochem Physiol B Biochem Mol Biol 128: 187‐204, 2001.
 28. Csanyi G, Taylor WR, Pagano PJ. NOX and inflammation in the vascular adventitia. Free Radic Biol Med 47: 1254‐1266, 2009.
 29. Cummins EP, Taylor CT. Hypoxia‐responsive transcription factors. Pflugers Arch 450: 363‐371, 2005.
 30. da Silva Meirelles L, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post‐natal organs and tissues. J Cell Sci 119: 2204‐2213, 2006.
 31. Das M, Bouchey DM, Moore MJ, Hopkins DC, Nemenoff RA, Stenmark KR. Hypoxia‐induced proliferative response of vascular adventitial fibroblasts is dependent on g protein‐mediated activation of mitogen‐activated protein kinases. J Biol Chem 276: 15631‐15640, 2001.
 32. Das M, Burns N, Wilson SJ, Zawada WM, Stenmark KR. Hypoxia exposure induces the emergence of fibroblasts lacking replication repressor signals of PKCzeta in the pulmonary artery adventitia. Cardiovasc Res 78: 440‐448, 2008.
 33. Das M, Dempsey EC, Bouchey D, Reyland ME, Stenmark KR. Chronic hypoxia induces exaggerated growth responses in pulmonary artery adventitial fibroblasts: potential contribution of specific protein kinase c isozymes. Am J Respir Cell Mol Biol 22: 15‐25, 2000.
 34. Das M, Dempsey EC, Reeves JT, Stenmark KR. Selective expansion of fibroblast subpopulations from pulmonary artery adventitia in response to hypoxia. Am J Physiol Lung Cell Mol Physiol 282: L976‐L986, 2002.
 35. Davie NJ, Crossno JT Jr., Frid MG, Hofmeister SE, Reeves JT, Hyde DM, Carpenter TC, Brunetti JA, McNiece IK, Stenmark KR. Hypoxia‐induced pulmonary artery adventitial remodeling and neovascularization: contribution of progenitor cells. Am J Physiol Lung Cell Mol Physiol 286: L668‐L678, 2004.
 36. Davie NJ, Gerasimovskaya EV, Hofmeister SE, Richman AP, Jones PL, Reeves JT, Stenmark KR. Pulmonary artery adventitial fibroblasts cooperate with vasa vasorum endothelial cells to regulate vasa vasorum neovascularization: A process mediated by hypoxia and endothelin‐1. Am J Pathol 168: 1793‐1807, 2006.
 37. Desmouliere A, Chaponnier C, Gabbiani G. Tissue repair, contraction, and the myofibroblast. Wound Repair Regen 13: 7‐12, 2005.
 38. Desmouliere A, Guyot C, Gabbiani G. The stroma reaction myofibroblast: A key player in the control of tumor cell behavior. Int J Dev Biol 48: 509‐517, 2004.
 39. Dorfmuller P, Perros F, Balabanian K, Humbert M. Inflammation in pulmonary arterial hypertension. Eur Respir J 22: 358‐363, 2003.
 40. Durmowicz AG, Orton EC, Stenmark KR. Progressive loss of vasodilator responsive component of pulmonary hypertension in neonatal calves exposed to 4,570 m. Am J Physiol 265: H2175‐H2183, 1993.
 41. Durmowicz AG, Parks WC, Hyde DM, Mecham RP, Stenmark KR. Persistence, re‐expression, and induction of pulmonary arterial fibronectin, tropoelastin, and type I procollagen mRNA expression in neonatal hypoxic pulmonary hypertension. Am J Pathol 145: 1411‐1420, 1994.
 42. Egeblad M, Littlepage LE, Werb Z. The fibroblastic coconspirator in cancer progression. Cold Spring Harb Symp Quant Biol 70: 383‐388, 2005.
 43. Esteller M. Epigenetics in cancer. N Engl J Med 358: 1148‐1159, 2008.
 44. Eul B, Rose F, Krick S, Savai R, Goyal P, Klepetko W, Grimminger F, Weissmann N, Seeger W, Hanze J. Impact of HIF‐1alpha and HIF‐2alpha on proliferation and migration of human pulmonary artery fibroblasts in hypoxia. FASEB J 20: 163‐165, 2006.
 45. Eyden B. Fibroblast phenotype plasticity: Relevance for understanding heterogeneity in “fibroblastic” tumors. Ultrastruct Pathol 28: 307‐319, 2004.
 46. Eyden B. The myofibroblast: A study of normal, reactive and neoplastic tissues, with an emphasis on ultrastructure, Part 1: Normal and reactive cells. J Submicrosc Cytol Pathol 37: 109‐204, 2005.
 47. Firestein GS, Alvaro‐Gracia JM, Maki R. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol 144: 3347‐3353, 1990.
 48. Flavell SJ, Hou TZ, Lax S, Filer AD, Salmon M, Buckley CD. Fibroblasts as novel therapeutic targets in chronic inflammation. Br J Pharmacol 153 (suppl 1): S241‐S246, 2008.
 49. Frid M, Brunetti J, Burke D, Carpenter T, Davie N, Reeves J, Roedersheimer M, van Rooijen N, Stenmark K. Hypoxia‐induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of monocyte/macrophage lineage. Am J Pathol 168: 659‐669, 2006.
 50. Frid MG, Brunetti JA, Burke DL, Carpenter TC, Davie NJ, Reeves JT, Roedersheimer MT, van Rooijen N, Stenmark KR. Hypoxia‐induced pulmonary vascular remodeling requires recruitment of circulating mesenchymal precursors of a monocyte/macrophage lineage. Am J Pathol 168: 659‐669, 2006.
 51. 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 pro‐mitogenic potentials within the distal pulmonary artery wall. Am J Physiol Lung Cell Mol Physiol 297(6): L1059‐L1072, 2009.
 52. Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA, Ruadkow IA. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 2: 83‐92, 1974.
 53. Gabbiani G. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200: 500‐503, 2003.
 54. Gallucci RM, Lee EG, Tomasek JJ. IL‐6 modulates alpha‐smooth muscle actin expression in dermal fibroblasts from IL‐6‐deficient mice. J Invest Dermatol 126: 561‐568, 2006.
 55. Gao PJ, Li Y, Sun AJ, Liu JJ, Ji KD, Zhang YZ, Sun WL, Marche P, Zhu DL. Differentiation of vascular myofibroblasts induced by transforming growth factor‐beta1 requires the involvement of protein kinase Calpha. J Mol Cell Cardiol 35: 1105‐1112, 2003.
 56. Gebb SA, Jones PL. Hypoxia and lung branching morphogenesis. Adv Exp Med Biol 543: 117‐125, 2003.
 57. 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.
 58. Gerasimovskaya EV, Tucker DA, Stenmark KR. Activation of phosphatidylinositol 3‐kinase, Akt, and mammalian target of rapamycin is necessary for hypoxia‐induced pulmonary artery adventitial fibroblast proliferation. J Appl Physiol 98: 722‐731, 2005.
 59. Gonzalez MC, Arribas SM, Molero F, Fernandez‐Alfonso MS. Effect of removal of adventitia on vascular smooth muscle contraction and relaxation. Am J Physiol Heart Circ Physiol 280: H2876‐H2881, 2001.
 60. Gossl M, Rosol M, Malyar NM, Fitzpatrick LA, Beighley PE, Zamir M, Ritman EL. Functional anatomy and hemodynamic characteristics of vasa vasorum in the walls of porcine coronary arteries. Anat Rec 272: 526‐537, 2003.
 61. Hagood JS, Lasky JA, Nesbitt JE, Segarini P. Differential expression, surface binding, and response to connective tissue growth factor in lung fibroblast subpopulations. Chest 120: 64S‐66S, 2001.
 62. Hagood JS, Prabhakaran P, Kumbla P, Salazar L, MacEwen MW, Barker TH, Ortiz LA, Schoeb T, Siegal GP, Alexander CB, Pardo A, Selman M. Loss of fibroblast Thy‐1 expression correlates with lung fibrogenesis. Am J Pathol 167: 365‐379, 2005.
 63. Han CI, Campbell GR, Campbell JH. Circulating bone marrow cells can contribute to neointimal formation. J Vasc Res 38: 113‐119, 2001.
 64. Han JW, Shimada K, Ma‐Krupa W, Johnson TL, Nerem RM, Goronzy JJ, Weyand CM. Vessel wall‐embedded dendritic cells induce T‐cell autoreactivity and initiate vascular inflammation. Circ Res 102: 546‐553, 2008.
 65. Hardie WD, Glasser SW, Hagood JS. Emerging concepts in the pathogenesis of lung fibrosis. Am J Pathol 175: 3‐16, 2009.
 66. Hartlapp I, Abe R, Saeed RW, Peng T, Voelter W, Bucala R, Metz CN. Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo. FASEB J 15: 2215‐2224, 2001.
 67. Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Kawabe T, Shimokata K, Hasegawa Y. Endothelial‐mesenchymal transition in bleomycin‐induced pulmonary fibrosis. Am J Respir Cell Mol Biol 43: 161‐172, 2010.
 68. Hassoun PM, Mouthon L, Barbera 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 remodeling. J Am Coll Cardiol 54: S10‐S19, 2009.
 69. Haurani MJ, Pagano PJ. Adventitial fibroblast reactive oxygen species as autocrine and paracrine mediators of remodeling: Bellwether for vascular disease? Cardiovasc Res 75: 679‐689, 2007.
 70. Hayden MR, Tyagi SC. Vasa vasorum in plaque angiogenesis, metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: A malignant transformation. Cardiovasc Diabetol 3: 1, 2004.
 71. Herget J, Novotna J, Bibova J, Povysilova V, Vankova M, Hampl V. Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 285: L199‐L208, 2003.
 72. Herrmann J, Best PJ, Ritman EL, Holmes DR, Lerman LO, Lerman A. Chronic endothelin receptor antagonism prevents coronary vasa vasorum neovascularization in experimental hypercholesterolemia. J Am Coll Cardiol 39: 1555‐1561, 2002.
 73. Herrmann J, Samee S, Chade A, Porcel MR, Lerman LO, Lerman A. Differential effect of experimental hypertension and hypercholesterolemia on adventitial remodeling. Arterioscler Thromb Vasc Biol 25: 447‐453, 2005.
 74. Hillebrands J, Van Den Hurk BM, Klatter FA, Popa ER, Nieuwenhuis P, Rozing J. Recipient origin of neointimal vascular smooth muscle cells in cardiac allografts with transplant arteriosclerosis. J Heart Lung Transplant 19: 1183‐1192, 2000.
 75. Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol 127: 526‐537, 2007.
 76. Hlatky L, Tsionou C, Hahnfeldt P, Coleman CN. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia‐induced vascular endothelial growth factor up‐regulation and protein expression. Cancer Res 54: 6083‐6086, 1994.
 77. Hogaboam CM, Bone‐Larson CL, Lipinski S, Lukacs NW, Chensue SW, Strieter RM, Kunkel SL. Differential monocyte chemoattractant protein‐1 and chemokine receptor 2 expression by murine lung fibroblasts derived from Th1‐ and Th2‐type pulmonary granuloma models. J Immunol 163: 2193‐2201, 1999.
 78. Hoshino A, Chiba H, Nagai K, Ishii G, Ochiai A. Human vascular adventitial fibroblasts contain mesenchymal stem/progenitor cells. Biochem Biophys Res Commun 368: 305‐310, 2008.
 79. Hu Y, Davison F, Zhang Z, Xu Q. Endothelial replacement and angiogenesis in arteriosclerotic lesions of allografts are contributed by circulating progenitor cells. Circulation 108: 3122‐3127, 2003.
 80. Hu Y, Zhang Z, Torsney E, Afzal AR, Davison F, Metzler B, Xu Q. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE‐deficient mice. J Clin Invest 113: 1258‐1265, 2004.
 81. 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: 13S‐24S, 2004.
 82. Jabs A, Okamoto E, Vinten‐Johansen J, Bauriedel G, Wilcox JN. Sequential patterns of chemokine‐ and chemokine receptor‐synthesis following vessel wall injury in porcine coronary arteries. Atherosclerosis 192: 75‐84, 2007.
 83. Jelaska A, Strehlow D, Korn JH. Fibroblast heterogeneity in physiological conditions and fibrotic disease. Springer Semin Immunopathol 21: 385‐395, 1999.
 84. Jian B, Jones PL, Li Q, Mohler ER III, Schoen FJ, Levy RJ. Matrix metalloproteinase‐2 is associated with tenascin‐C in calcific aortic stenosis. Am J Pathol 159: 321‐327, 2001.
 85. Jin ZG, Melaragno MG, Liao DF, Yan C, Haendeler J, Suh YA, Lambeth JD, Berk BC. Cyclophilin A is a secreted growth factor induced by oxidative stress. Circ Res 87: 789‐796, 2000.
 86. Johnnidis JB, Harris MH, Wheeler RT, Stehling‐Sun S, Lam MH, Kirak O, Brummelkamp TR, Fleming MD, Camargo FD. Regulation of progenitor cell proliferation and granulocyte function by microRNA‐223. Nature 451: 1125‐1129, 2008.
 87. Jones FS, Jones PL. The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling. Dev Dyn 218: 235‐259, 2000.
 88. Jones FS, Meech R, Edelman DB, Oakey RJ, Jones PL. Prx1 controls vascular smooth muscle cell proliferation and tenascin‐C expression and is upregulated with Prx2 in pulmonary vascular disease. Circ Res 89: 131‐138, 2001.
 89. 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.
 90. Jordana M, Schulman J, McSharry C, Irving LB, Newhouse MT, Jordana G, Gauldie J. Heterogeneous proliferative characteristics of human adult lung fibroblast lines and clonally derived fibroblasts from control and fibrotic tissue. Am Rev Respir Dis 137: 579‐584, 1988.
 91. Kadowitz PJ, Hyman AL. Effect of sympathetic nerve stimulation on pulmonary vascular resistance in the dog. Circ Res 32: 221‐227, 1973.
 92. Kadowitz PJ, Knight DS, Hibbs RG, Ellison JP, Joiner PD, Brody MJ, Hyman AL. Influence of 5‐ and 6‐hydroxydopamine on adrenergic transmission and nerve terminal morphology in the canine pulmonary vascular bed. Circ Res 39: 191‐199, 1976.
 93. Kalluri R, Neilson EG. Epithelial‐mesenchymal transition and its implications for fibrosis. J Clin Invest 112: 1776‐1784, 2003.
 94. Kalluri R, Weinberg RA. The basics of epithelial‐mesenchymal transition. J Clin Invest 119: 1420‐1428, 2009.
 95. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev 6: 392‐401, 2006.
 96. Kantachuvesiri S, Fleming S, Peters J, Peters B, Brooker G, Lammie AG, McGrath I, Kotelevtsev Y, Mullins JJ. Controlled hypertension, a transgenic toggle switch reveals differential mechanisms underlying vascular disease. J Biol Chem 276: 36727‐36733, 2001.
 97. Karouzakis E, Gay RE, Michel BA, Gay S, Neidhart M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 60: 3613‐3622, 2009.
 98. Kimura H, Okada O, Tanabe N, Tanaka Y, Terai M, Takiguchi Y, Masuda M, Nakajima N, Hiroshima K, Inadera H, Matsushima K, Kuriyama T. Plasma monocyte chemoattractant protein‐1 and pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 164: 319‐324, 2001.
 99. Kottmann RM, Hogan CM, Phipps RP, Sime PJ. Determinants of initiation and progression of idiopathic pulmonary fibrosis. Respirology 14: 917‐933, 2009.
 100. Krick S, Hanze J, Eul B, Savai R, Seay U, Grimminger F, Lohmeyer J, Klepetko W, Seeger W, Rose F. Hypoxia‐driven proliferation of human pulmonary artery fibroblasts: Cross‐talk between HIF‐1alpha and an autocrine angiotensin system. FASEB J 19: 857‐859, 2005.
 101. Kroon ME, Koolwijk P, Van Der Vecht B, van Hinsbergh VW. Hypoxia in combination with FGF‐2 induces tube formation by human microvascular endothelial cells in a fibrin matrix: Involvement of at least two signal transduction pathways. J Cell Sci 114: 825‐833, 2001.
 102. Lafyatis R, Remmers EF, Roberts AB, Yocum DE, Sporn MB, Wilder RL. Anchorage‐independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous platelet‐derived growth factor and inhibition by transforming growth factor‐beta and retinoids J Clin Invest 83: 1267‐1276, 1989.
 103. Langheinrich AC, Kampschulte M, Buch T, Bohle RM. Vasa vasorum and atherosclerosis—quid novi? Thromb Haemost 97: 873‐879, 2007.
 104. Langleben D, Szarek JL, Coflesky JT, Jones RC, Reid LM, Evans JN. Altered artery mechanics and structure in monocrotaline pulmonary hypertension. J Appl Physiol 65: 2326‐2331, 1988.
 105. Li G, Chen SJ, Oparil S, Chen YF, Thompson JA. Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries. Circulation 101: 1362‐1365, 2000.
 106. Li S, Tabar SS, Malec V, Eul BG, Klepetko W, Weissmann N, Grimminger F, Seeger W, Rose F, Hanze J. NOX4 regulates ROS levels under normoxic and hypoxic conditions, triggers proliferation, and inhibits apoptosis in pulmonary artery adventitial fibroblasts. Antioxid Redox Signal 10: 1687‐1698, 2008.
 107. Liu C, Nath KA, Katusic ZS, Caplice NM. Smooth muscle progenitor cells in vascular disease. Trends Cardiovasc Med 14: 288‐293, 2004.
 108. Liu J, Ormsby A, Oja‐Tebbe N, Pagano PJ. Gene transfer of NAD(P)H oxidase inhibitor to the vascular adventitia attenuates medial smooth muscle hypertrophy. Circ Res 95: 587‐594, 2004.
 109. Liu JQ, Zelko IN, Erbynn EM, Sham JS, Folz RJ. Hypoxic pulmonary hypertension: Role of superoxide and NADPH oxidase (gp91phox). Am J Physiol Lung Cell Mol Physiol 290: L2‐L10, 2006.
 110. Liu T, Chung MJ, Ullenbruch M, Yu H, Jin H, Hu B, Choi YY, Ishikawa F, Phan SH. Telomerase activity is required for bleomycin‐induced pulmonary fibrosis in mice. J Clin Invest 117: 3800‐3809, 2007.
 111. Liu T, Dhanasekaran SM, Jin H, Hu B, Tomlins SA, Chinnaiyan AM, Phan SH. FIZZ1 stimulation of myofibroblast differentiation. Am J Pathol 164: 1315‐1326, 2004.
 112. Lo D, Feng L, Li L, Carson MJ, Crowley M, Pauza M, Nguyen A, Reilly CR. Integrating innate and adaptive immunity in the whole animal. Immunol Rev 169: 225‐239, 1999.
 113. Ma‐Krupa W, Jeon MS, Spoerl S, Tedder TF, Goronzy JJ, Weyand CM. Activation of arterial wall dendritic cells and breakdown of self‐tolerance in giant cell arteritis. J Exp Med 199: 173‐183, 2004.
 114. Maiellaro K, Taylor WR. The role of the adventitia in vascular inflammation. Cardiovasc Res 75: 640‐648, 2007.
 115. Mallawaarachchi CM, Weissberg PL, Siow RC. Smad7 gene transfer attenuates adventitial cell migration and vascular remodeling after balloon injury. Arterioscler Thromb Vasc Biol 25: 1383‐1387, 2005.
 116. Mallawaarachchi CM, Weissberg PL, Siow RC. Antagonism of platelet‐derived growth factor by perivascular gene transfer attenuates adventitial cell migration after vascular injury: New tricks for old dogs? FASEB J 20: 1686‐1688, 2006.
 117. Malmstrom J, Lindberg H, Lindberg C, Bratt C, Wieslander E, Delander EL, Sarnstrand B, Burns JS, Mose‐Larsen P, Fey S, Marko‐Varga G. Transforming growth factor‐beta 1 specifically induce proteins involved in the myofibroblast contractile apparatus. Mol Cell Proteomics 3: 466‐477, 2004.
 118. Martin TA, Harding KG, Jiang WG. Regulation of angiogenesis and endothelial cell motility by matrix‐bound fibroblasts. Angiogenesis 3: 69‐76, 1999.
 119. Martin TA, Harding K, Jiang WG. Matrix‐bound fibroblasts regulate angiogenesis by modulation of VE‐cadherin. Eur J Clin Invest 31: 931‐938, 2001.
 120. McGrath JC, Deighan C, Briones AM, Shafaroudi MM, McBride M, Adler J, Arribas SM, Vila E, Daly CJ. New aspects of vascular remodelling: The involvement of all vascular cell types. Exp Physiol 90: 469‐475, 2005.
 121. Meyrick B, Reid L. Hypoxia and incorporation of 3H‐thymidine by cells of the rat pulmonary arteries and alveolar wall. Am J Pathol 96: 51‐70, 1979.
 122. Meyrick B, Reid L. Ultrastructural findings in lung biopsy material from children with congenital heart defects. Am J Pathol 101: 527‐542, 1980.
 123. Meyrick BO, Reid LM. Crotalaria‐induced pulmonary hypertension. Uptake of 3H‐thymidine by the cells of the pulmonary circulation and alveolar walls. Am J Pathol 106: 84‐94, 1982.
 124. Micke P, Hackbusch D, Mercan S, Stawowy P, Tsuprykov O, Unger T, Ostman A, Kappert K. Regulation of tyrosine phosphatases in the adventitia during vascular remodelling. Biochem Biophys Res Commun 382: 678‐684, 2009.
 125. Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E, Drexler S, Sofat N, Kashiwagi M, Orend G, Brennan F, Foxwell B. Tenascin‐C is an endogenous activator of Toll‐like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med 15: 774‐780, 2009.
 126. Mitzner W, Wagner EM. Vascular remodeling in the circulations of the lung. J Appl Physiol 97: 1999‐2004, 2004.
 127. Morrell NW, Atochina EN, Morris KG, Danilov SM, Stenmark KR. Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia‐induced pulmonary hypertension. J Clin Invest 96: 1823‐1833, 1995.
 128. Morrell NW, Morris KG, Stenmark KR. Role of angiotensin‐converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension. Am J Physiol 269: H1186‐H1194, 1995.
 129. Moulton KS, Vakili K, Zurakowski D, Soliman M, Butterfield C, Sylvin E, Lo KM, Gillies S, Javaherian K, Folkman J. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc Natl Acad Sci USA 100: 4736‐4741, 2003.
 130. Mueller MM, Fusenig NE. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4: 839‐849, 2004.
 131. Muro AF, Moretti FA, Moore BB, Yan M, Atrasz RG, Wilke CA, Flaherty KR, Martinez FJ, Tsui JL, Sheppard D, Baralle FE, Toews GB, White ES. An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am J Respir Crit Care Med 177: 638‐645, 2008.
 132. Nakatsu MN, Sainson RC, Aoto JN, Taylor KL, Aitkenhead M, Perez‐del‐Pulgar S, Carpenter PM, Hughes CC. Angiogenic sprouting and capillary lumen formation modeled by human umbilical vein endothelial cells (HUVEC) in fibrin gels: The role of fibroblasts and angiopoietin‐1. Microvasc Res 66: 102‐112, 2003.
 133. Nathan S, Noble P, Tuder R. Idiopathic pulmonary fibrosis and pulmonary hypertension: Connecting the dots. Am J Respir Crit Care Med 175: 875‐880, 2007.
 134. Neidhart M, Rethage J, Kuchen S, Kunzler P, Crowl RM, Billingham ME, Gay RE, Gay S. Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: Association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum 43: 2634‐2647, 2000.
 135. Nozaki Y, Liu T, Hatano K, Gharaee‐Kermani M, Phan SH. Induction of telomerase activity in fibroblasts from bleomycin‐injured lungs. Am J Respir Cell Mol Biol 23: 460‐465, 2000.
 136. Nozik‐Grayck E, Suliman HB, Majka S, Albietz J, Van Rheen Z, Roush K, Stenmark KR. Lung EC‐SOD overexpression attenuates hypoxic induction of Egr‐1 and chronic hypoxic pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 295: L422‐L430, 2008.
 137. Numano F. Vasa vasoritis, vasculitis and atherosclerosis. Int J Cardiol 75 (suppl 1): S1‐S8, discussion S17‐S19, 2000.
 138. O'Connell RM, Rao DS, Chaudhuri AA, Baltimore D. Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 10: 111‐122.
 139. Ogawa M, LaRue AC, Drake CJ. Hematopoietic origin of fibroblasts/myofibroblasts: Its pathophysiologic implications. Blood 108: 2893‐2896, 2006.
 140. Okada H, Kalluri R. Cellular and molecular pathways that lead to progression and regression of renal fibrogenesis. Curr Mol Med 5: 467‐474, 2005.
 141. Okamoto E, Couse T, De Leon H, Vinten‐Johansen J, Goodman RB, Scott NA, Wilcox JN. Perivascular inflammation after balloon angioplasty of porcine coronary arteries. Circulation 104: 2228‐2235, 2001.
 142. Orton EC, LaRue SM, Ensley B, Stenmark K. Bromodeoxyuridine labeling and DNA content of pulmonary arterial medial cells from hypoxia‐exposed and nonexposed healthy calves. Am J Vet Res 53: 1925‐1930, 1992.
 143. Pagano PJ, Chanock SJ, Siwik DA, Colucci WS, Clark JK. Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. Hypertension 32: 331‐337, 1998.
 144. Pagano PJ, Clark JK, Cifuentes‐Pagano ME, Clark SM, Callis GM, Quinn MT. Localization of a constitutively active, phagocyte‐like NADPH oxidase in rabbit aortic adventitia: Enhancement by angiotensin II. Proc Natl Acad Sci USA 94: 14483‐14488, 1997.
 145. Pap T, Muller‐Ladner U, Gay RE, Gay S. Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res 2: 361‐367, 2000.
 146. Passman JN, Dong XR, Wu SP, Maguire CT, Hogan KA, Bautch VL, Majesky MW. A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells. Proc Natl Acad Sci USA 105: 9349‐9354, 2008.
 147. Patel S, Shi Y, Niculescu R, Chung EH, Martin JL, Zalewski A. Characteristics of coronary smooth muscle cells and adventitial fibroblasts. Circulation 101: 524‐532, 2000.
 148. Perros F, Dorfmuller P, Souza R, Durand‐Gasselin I, Mussot S, Mazmanian M, Herve P, Emilie D, Simonneau G, Humbert M. Dendritic cell recruitment in lesions of human and experimental pulmonary hypertension. Eur Respir J 29: 462‐468, 2007.
 149. Phan SH. The myofibroblast in pulmonary fibrosis. Chest 122: 286S‐289S, 2002.
 150. Phan SH. Fibroblast phenotypes in pulmonary fibrosis. Am J Respir Cell Mol Biol 29: S87‐S92, 2003.
 151. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 114: 438‐446, 2004.
 152. Phipps RE. Pulmonary Fibroblast Heterogeneity. Boca Raton, FL: CRC Press, 1992.
 153. Phipps RP, Penney DP, Keng P, Quill H, Paxhia A, Derdak S, Felch ME. Characterization of two major populations of lung fibroblasts: Distinguishing morphology and discordant display of Thy 1 and class II MHC. Am J Respir Cell Mol Biol 1: 65‐74, 1989.
 154. Pinto RF, Higuchi Mde L, Aiello VD. Decreased numbers of T‐lymphocytes and predominance of recently recruited macrophages in the walls of peripheral pulmonary arteries from 26 patients with pulmonary hypertension secondary to congenital cardiac shunts. Cardiovasc Pathol 13: 268‐275, 2004.
 155. Popovici RM, Irwin JC, Giaccia AJ, Giudice LC. Hypoxia and cAMP stimulate vascular endothelial growth factor (VEGF) in human endometrial stromal cells: potential relevance to menstruation and endometrial regeneration. J Clin Endocrinol Metab 84: 2245‐2248, 1999.
 156. Postlethwaite AE, Shigemitsu H, Kanangat S. Cellular origins of fibroblasts: Possible implications for organ fibrosis in systemic sclerosis. Curr Opin Rheumatol 16: 733‐738, 2004.
 157. Potenta S, Zeisberg E, Kalluri R. The role of endothelial‐to‐mesenchymal transition in cancer progression. Br J Cancer 99: 1375‐1379, 2008.
 158. Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science (New York) 276: 71‐74, 1997.
 159. Prockop DJ, Kivirikko KI. Collagens: Molecular biology, diseases, and potentials for therapy. Annu Rev Biochem 64: 403‐434, 1995.
 160. Pryshchep O, Ma‐Krupa W, Younge BR, Goronzy JJ, Weyand CM. Vessel‐specific Toll‐like receptor profiles in human medium and large arteries. Circulation 118: 1276‐1284, 2008.
 161. Quan TE, Cowper S, Wu SP, Bockenstedt LK, Bucala R. Circulating fibrocytes: Collagen‐secreting cells of the peripheral blood. Int J Biochem Cell Biol 36: 598‐606, 2004.
 162. Radisky E, Radisky D. Stromal induction of breast cancer: Inflammation and invasion. Rev Endocr Metab Disord 8: 279‐287, 2007.
 163. Raghu G, Chen YY, Rusch V, Rabinovitch PS. Differential proliferation of fibroblasts cultured from normal and fibrotic human lungs. Am Rev Respir Dis 138: 703‐708, 1988.
 164. Raines EW. The extracellular matrix can regulate vascular cell migration, proliferation, and survival: Relationships to vascular disease. Int J Exp Pathol 81: 173‐182, 2000.
 165. Rege TA, Pallero MA, Gomez C, Grenett HE, Murphy‐Ullrich JE, Hagood JS. Thy‐1, via its GPI anchor, modulates Src family kinase and focal adhesion kinase phosphorylation and subcellular localization, and fibroblast migration, in response to thrombospondin‐1/hep I. Exp Cell Res 312: 3752‐3767, 2006.
 166. Rey FE, Pagano PJ. The reactive adventitia: Fibroblast oxidase in vascular function. Arterioscler Thromb Vasc Biol 22: 1962‐1971, 2002.
 167. Ritman EL, Lerman A. The dynamic vasa vasorum. Cardiovasc Res 75: 649‐658, 2007.
 168. Rondelet B, Kerbaul F, Van Beneden R, Hubloue I, Huez S, Fesler P, Remmelink M, Brimioulle S, Salmon I, Naeije R. Prevention of pulmonary vascular remodelling and of decreased BMPR‐2 expression by losartan therapy in shunt‐induced pulmonary hypertension. Am J Physiol Heart Circ Physiol 289(6): H2319–H2324, 2005.
 169. Ronty MJ, Leivonen SK, Hinz B, Rachlin A, Otey CA, Kahari VM, Carpen OM. Isoform‐specific regulation of the actin‐organizing protein palladin during TGF‐beta1‐induced myofibroblast differentiation. J Invest Dermatol 126: 2387‐2396, 2006.
 170. Rose F, Grimminger F, Appel J, Heller M, Pies V, Weissmann N, Fink L, Schmidt S, Krick S, Camenisch G, Gassmann M, Seeger W, Hanze J. Hypoxic pulmonary artery fibroblasts trigger proliferation of vascular smooth muscle cells: Role of hypoxia‐inducible transcription factors. FASEB J 16: 1660‐1661, 2002.
 171. Rosenbloom J, Abrams WR, Mecham R. Extracellular matrix 4: The elastic fiber. FASEB J 7: 1208‐1218, 1993.
 172. Sahara M, Sata M, Morita T, Nakamura K, Hirata Y, Nagai R. Diverse contribution of bone marrow‐derived cells to vascular remodeling associated with pulmonary arterial hypertension and arterial neointimal formation. Circulation 115: 509‐517, 2007.
 173. 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.
 174. Sata M, Saiura A, Kunisato A, Tojo A, Okada S, Tokuhisa T, Hirai H, Makuuchi M, Hirata Y, Nagai R. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 8: 403‐409, 2002.
 175. Schmidt M, Sun G, Stacey MA, Mori L, Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. J Immunol 171: 380‐389, 2003.
 176. Schulze‐Bauer CA, Regitnig P, Holzapfel GA. Mechanics of the human femoral adventitia including the high‐pressure response. Am J Physiol Heart Circ Physiol 282: H2427‐H2440, 2002.
 177. 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: 2178‐2187, 1996.
 178. Sharkey AM, Day K, McPherson A, Malik S, Licence D, Smith SK, Charnock‐Jones DS. Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. J Clin Endocrinol Metab 85: 402‐409, 2000.
 179. Shi Y, Niculescu R, Wang D, Patel S, Davenpeck KL, Zalewski A. Increased NAD(P)H oxidase and reactive oxygen species in coronary arteries after balloon injury. Arterioscler Thromb Vasc Biol 21: 739‐745, 2001.
 180. 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: 1655‐1664, 1996.
 181. Shi Y, O'Brien JE Jr., Fard A, Zalewski A. Transforming growth factor‐beta 1 expression and myofibroblast formation during arterial repair. Arterioscler Thromb Vasc Biol 16: 1298‐1305, 1996.
 182. Shi Y, Patel S, Niculescu R, Chung W, Desrochers P, Zalewski A. Role of matrix metalloproteinases and their tissue inhibitors in the regulation of coronary cell migration. Arterioscler Thromb Vasc Biol 19: 1150‐1155, 1999.
 183. Shi‐Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou‐Gharios G, Pearson JD, Dashwood M, du Bois RM, Black CM, Leask A, Abraham DJ. Endothelin‐1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3‐kinase/Akt‐dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell 15: 2707‐2719, 2004.
 184. Short M, Fox S, Lam F, Stenmark K, Das M. Hypoxia‐induced proliferative responses of vascular adventitital fibroblasts: Role of PKC‐zeta and MAP kinase phosphatases‐1. In: Protein Phosphorylation and Cell Signaling. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2005.
 185. Short M, Fox S, Stenmark K, Das M. Hypoxia‐induced alterations in PKC‐zeta signaling result in augmented fibroblast proliferation. In: Aspen Lung Conference, Aspen, CO, 2004.
 186. Short M, Nemenoff RA, Zawada WM, Stenmark KR, Das M. Hypoxia induces differentiation of pulmonary artery adventitial fibroblasts into myofibroblasts. Am J Physiol Cell Physiol 286: C416‐C425, 2004.
 187. Short MD, Fox SM, Lam CF, Stenmark KR, Das M. Protein kinase Czeta attenuates hypoxia‐induced proliferation of fibroblasts by regulating MAP kinase phosphatase‐1 expression. Mol Biol Cell 17: 1995‐2008, 2006.
 188. Shuttleworth CA. Type VIII collagen. Int J Biochem Cell Biol 29: 1145‐1148, 1997.
 189. Silver FH, Horvath I, Foran DJ. Viscoelasticity of the vessel wall: The role of collagen and elastic fibers. Crit Rev Biomed Eng 29: 279‐301, 2001.
 190. Siow RC, Mallawaarachchi CM, Weissberg PL. Migration of adventitial myofibroblasts following vascular balloon injury: Insights from in vivo gene transfer to rat carotid arteries. Cardiovasc Res 59: 212‐221, 2003.
 191. Smith P, Heath D, Yacoub M, Madden B, Caslin A, Gosney J. The ultrastructure of plexogenic pulmonary arteriopathy. J Pathol 160: 111‐121, 1990.
 192. Smith PJ, Teichert‐Kuliszewska K, Monge JC, Stewart DJ. Regulation of endothelin‐B receptor mRNA expression in human endothelial cells by cytokines and growth factors. J Cardiovasc Pharmacol 31 (suppl 1): S158‐S160, 1998.
 193. Smith RS, Smith TJ, Blieden TM, and Phipps RP. Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation. Am J Pathol 151: 317‐322, 1997.
 194. Sobin SS, Tremer HM, Hardy JD, Chiodi HP. Changes in arteriole in acute and chronic hypoxic pulmonary hypertension and recovery in rat. J Appl Physiol 55: 1445‐1455, 1983.
 195. Sorrell JM, Caplan AI. Fibroblast heterogeneity: More than skin deep. J Cell Sci 117: 667‐675, 2004.
 196. Sorrell JM, Caplan AI. Fibroblasts—a diverse population at the center of it all. Int Rev Cell Mol Biol 276: 161‐214, 2009.
 197. Steinman RM, Inaba K. Myeloid dendritic cells. J Leukoc Biol 66: 205‐208, 1999.
 198. Stenmark K, Durmowicz A, Dempsey EC. Modulation of Vascular Wall Cell Phenotype in Pulmonary Hypertension. London: Portland Press, 1995.
 199. Stenmark KR, Davie N, Frid M, Gerasimovskaya E, Das M. Role of the adventitia in pulmonary vascular remodeling. Physiology (Bethesda) 21: 134‐145, 2006.
 200. Stenmark KR, Davie NJ, Reeves JT, Frid MG. Hypoxia, leukocytes, and the pulmonary circulation. J Appl Physiol 98: 715‐721, 2005.
 201. Stenmark KR, Gerasimovskaya E, Nemenoff RA, Das M. Hypoxic activation of adventitial fibroblasts: Role in vascular remodeling. Chest 122: 326S‐334S, 2002.
 202. Stenmark KR, Mecham RP. Cellular and molecular mechanisms of pulmonary vascular remodeling. Annu Rev Physiol 59: 89‐144, 1997.
 203. 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: 783‐791, 2008.
 204. Strieter RM, Keeley EC, Burdick MD, Mehrad B. The role of circulating mesenchymal progenitor cells, fibrocytes, in promoting pulmonary fibrosis. Trans Am Clin Climatol Assoc 120: 49‐59, 2009.
 205. Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA. Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase. Proc Natl Acad Sci USA 102: 437‐442, 2005.
 206. Takami N, Osawa K, Miura Y, Komai K, Taniguchi M, Shiraishi M, Sato K, Iguchi T, Shiozawa K, Hashiramoto A, Shiozawa S. Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum 54: 779‐787, 2006.
 207. Tamaoki M, Imanaka‐Yoshida K, Yokoyama K, Nishioka T, Inada H, Hiroe M, Sakakura T, Yoshida T. Tenascin‐C regulates recruitment of myofibroblasts during tissue repair after myocardial injury. Am J Pathol 167: 71‐80, 2005.
 208. Tille JC, Pepper MS. Mesenchymal cells potentiate vascular endothelial growth factor‐induced angiogenesis in vitro. Exp Cell Res 280: 179‐191, 2002.
 209. Tonks NK. Redox redux: Revisiting PTPs and the control of cell signaling. Cell 121: 667‐670, 2005.
 210. Torry DJ, Richards CD, Podor TJ, Gauldie J. Anchorage‐independent colony growth of pulmonary fibroblasts derived from fibrotic human lung tissue. J Clin Invest 93: 1525‐1532, 1994.
 211. Torsney E, Hu Y, Xu Q. Adventitial progenitor cells contribute to arteriosclerosis. Trends Cardiovasc Med 15: 64‐68, 2005.
 212. Touyz RM, Schiffrin EL. Reactive oxygen species in vascular biology: Implications in hypertension. Histochem Cell Biol 122: 339‐352, 2004.
 213. Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, Rosenblatt RL, Shay JW, Garcia CK. Adult‐onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci USA 104: 7552‐7557, 2007.
 214. Tuder RM. Pathology of pulmonary arterial hypertension. Semin Respir Crit Care Med 30: 376‐385, 2009.
 215. Tuder RM, Marecki JC, Richter A, Fijalkowska I, Flores S. Pathology of pulmonary hypertension. Clin Chest Med 28: 23‐42, vii, 2007.
 216. van Rooij E, Sutherland LB, Thatcher JE, DiMaio JM, Naseem RH, Marshall WS, Hill JA, Olson EN. Dysregulation of microRNAs after myocardial infarction reveals a role of miR‐29 in cardiac fibrosis. Proc Natl Acad Sci USA 105: 13027‐13032, 2008.
 217. Velazquez OC, Snyder R, Liu ZJ, Fairman RM, Herlyn M. Fibroblast‐dependent differentiation of human microvascular endothelial cells into capillary‐like 3‐dimensional networks. FASEB J 16: 1316‐1318, 2002.
 218. Verity MA, Bevan JA. Fine structural study of the terminal effector plexus, neuromuscular and intermuscular relationships in the pulmonary artery. J Anat 103: 49‐63, 1968.
 219. 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 remodeling in rats. Hum Gene Ther 14: 861‐869, 2003.
 220. Virchow R. Die cellularpathologie in ltrer begruendung auf physiologische und pathologische gewebelehre. Berlin, 1858.
 221. Voelkel NF, Cool C. Pathology of pulmonary hypertension. Cardiol Clin 22: 343‐351, v, 2004.
 222. Von Euler US, Lishajko F. Catechol amines in the vascular wall. Acta Physiol Scand 42: 333‐341, 1958.
 223. Wallner K, Sharifi BG, Shah PK, Noguchi S, DeLeon H, Wilcox JN. Adventitial remodeling after angioplasty is associated with expression of tenascin mRNA by adventitial myofibroblasts. J Am Coll Cardiol 37: 655‐661, 2001.
 224. Wang HD, Xu S, Johns DG, Du Y, Quinn MT, Cayatte AJ, Cohen RA. Role of NADPH oxidase in the vascular hypertrophic and oxidative stress response to angiotensin II in mice. Circ Res 88: 947‐953, 2001.
 225. Welsh DJ, Peacock AJ, MacLean M, Harnett M. Chronic hypoxia induces constitutive p38 mitogen‐activated protein kinase activity that correlates with enhanced cellular proliferation in fibroblasts from rat pulmonary but not systemic arteries. Am J Respir Crit Care Med 164: 282‐289, 2001.
 226. Welsh DJ, Scott P, Plevin R, Wadsworth R, Peacock AJ. Hypoxia enhances cellular proliferation and inositol 1,4, 5‐triphosphate generation in fibroblasts from bovine pulmonary artery but not from mesenteric artery. Am J Respir Crit Care Med 158: 1757‐1762, 1998.
 227. Welsh DJ, Scott PH, Peacock AJ. p38 MAP kinase isoform activity and cell cycle regulators in the proliferative response of pulmonary and systemic artery fibroblasts to acute hypoxia. Pulm Pharmacol Ther 19 (2): 128‐138, 2006.
 228. Wilasrusmee C, Ondocin P, Bruch D, Shah G, Kittur S, Wilasrusmee S, Kittur DS. Amelioration of cyclosporin A effect on microvasculature by endothelin inhibitor. Surgery 134: 384‐389, 2003.
 229. Wilcox JN, Okamoto EI, Nakahara KI, Vinten‐Johansen J. Perivascular responses after angioplasty which may contribute to postangioplasty restenosis: A role for circulating myofibroblast precursors? Ann N Y Acad Sci 947: 68‐90, discussion 90‐62, 2001.
 230. Wilcox JN, Waksman R, King SB, Scott NA. The role of the adventitia in the arterial response to angioplasty: The effect of intravascular radiation. Int J Radiat Oncol Biol Phys 36: 789‐796, 1996.
 231. Wolinsky H, Glagov S. Nature of species differences in the medial distribution of aortic vasa vasorum in mammals. Circ Res 20: 409‐421, 1967.
 232. Xia H, Diebold D, Nho R, Perlman D, Kleidon J, Kahm J, Avdulov S, Peterson M, Nerva J, Bitterman P, Henke C. Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. J Exp Med 205: 1659‐1672, 2008.
 233. Xia Y, Pauza ME, Feng L, Lo D. RelB regulation of chemokine expression modulates local inflammation. Am J Pathol 151: 375‐387, 1997.
 234. Yan SF, Lu J, Xu L, Zou YS, Tongers J, Kisiel W, Mackman N, Pinsky DJ, Stern DM. Pulmonary expression of early growth response‐1: Biphasic time course and effect of oxygen concentration. J Appl Physiol 88: 2303‐2309, 2000.
 235. Yang L, Scott PG, Giuffre J, Shankowsky HA, Ghahary A, Tredget EE. Peripheral blood fibrocytes from burn patients: Identification and quantification of fibrocytes in adherent cells cultured from peripheral blood mononuclear cells. Lab Invest 82: 1183‐1192, 2002.
 236. Yi ES, Kim H, Ahn H, Strother J, Morris T, Masliah E, Hansen LA, Park K, Friedman PJ. Distribution of obstructive intimal lesions and their cellular phenotypes in chronic pulmonary hypertension. A morphometric and immunohistochemical study. Am J Respir Crit Care Med 162: 1577‐1586, 2000.
 237. Young KC, Torres E, Hatzistergos KE, Hehre D, Suguihara C, Hare JM. Circ Res 104: 1293‐1301, 2009.
 238. Zalewski A, Shi Y. Vascular myofibroblasts. Lessons from coronary repair and remodeling. Arterioscler Thromb Vasc Biol 17: 417‐422, 1997.
 239. Zebedee Z, Hara E. Id proteins in cell cycle control and cellular senescence. Oncogene 20: 8317‐8325, 2001.
 240. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R. Endothelial‐to‐mesenchymal transition contributes to cardiac fibrosis. Nat Med 13: 952‐961, 2007.
 241. Zengin E, Chalajour F, Gehling UM, Ito WD, Treede H, Lauke H, Weil J, Reichenspurner H, Kilic N, Ergun S. Vascular wall resident progenitor cells: A source for postnatal vasculogenesis. Development (Cambridge) 133: 1543‐1551, 2006.
 242. Zhou Y, Hagood JS, Murphy‐Ullrich JE. Thy‐1 expression regulates the ability of rat lung fibroblasts to activate transforming growth factor‐beta in response to fibrogenic stimuli. Am J Pathol 165: 659‐669, 2004.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Kurt R. Stenmark, Eva Nozik‐Grayck, Evgenia Gerasimovskaya, Adil Anwar, Min Li, Suzette Riddle, Maria Frid. The Adventitia: Essential Role in Pulmonary Vascular Remodeling. Compr Physiol 2010, 1: 141-161. doi: 10.1002/cphy.c090017