Comprehensive Physiology Wiley Online Library

Physiological Role of Vascular Endothelial Growth Factors as Homeostatic Regulators

Full Article on Wiley Online Library


The vascular endothelial growth factor (VEGF) family of proteins are key regulators of physiological systems. Originally linked with endothelial function, they have since become understood to be principal regulators of multiple tissues, both through their actions on vascular cells, but also through direct actions on other tissue types, including epithelial cells, neurons, and the immune system. The complexity of the five members of the gene family in terms of their different splice isoforms, differential translation, and specific localizations have enabled tissues to use these potent signaling molecules to control how they function to maintain their environment. This homeostatic function of VEGFs has been less intensely studied than their involvement in disease processes, development, and reproduction, but they still play a substantial and significant role in healthy control of blood volume and pressure, interstitial volume and drainage, renal and lung function, immunity, and signal processing in the peripheral and central nervous system. The widespread expression of VEGFs in healthy adult tissues, and the disturbances seen when VEGF signaling is inhibited support this view of the proteins as endogenous regulators of normal physiological function. This review summarizes the evidence and recent breakthroughs in understanding of the physiology that is regulated by VEGF, with emphasis on the role they play in maintaining homeostasis. © 2017 American Physiological Society. Compr Physiol 8:955‐979, 2018.

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. Schematic of the VEGF receptors. VEGFR1 and VEGFR2 both have seven IgG domains, and when they bind VEGF act as homodimers. The intracellular domain contains a kinase insert domain, and the receptors can heterodimerize. VEGFR3 is a similar receptor but is proteolytically cleaved during synthesis, and held together with a disulfine bond between IgG 4 and 5. The coreceptors NP1 and NP2 interact with the VEGF receptors to aid signaling, intracellular sorting, and recycling to the membrane. VEGF‐B and PlGF both bind only to VEGFR1, VEGF‐A binds both VEGFR1 and VEGFR2 and VEGF‐C, and VEGF‐D bind to VEGFR3, but when proteolytically processed increase their affinity for VEGFR2.
Figure 2. Figure 2. Splicing of the VEGF‐A gene. The eight exons are differentially spliced to form multiple isoforms in two primary families, the proangiogenic VEGF‐Axxx, which use the proximal splice site in exon 8, and the partial agonist VEGF‐Axxxb family, which can prevent VEGF‐Axxx‐mediated angiogenesis, but can signal to prevent cytotoxicity through partial activation of VEGFR2.
Figure 3. Figure 3. Coverage of endothelial fenestrations by glycocalyx. Induction of fenestrations has been shown by VEGF, and VEGF knockdown in the glomerulus reduces fenestrations in glomerular endothelial cells. The endothelial cells, including the fenestrations, are covered with a glycocalyx (imaged in (A) using electron tomography transmission electron microscopy) (9). (B) In diabetes the glycocalyx is lost, but can be restored by treatment with VEGF‐A165b (206).

Figure 1. Schematic of the VEGF receptors. VEGFR1 and VEGFR2 both have seven IgG domains, and when they bind VEGF act as homodimers. The intracellular domain contains a kinase insert domain, and the receptors can heterodimerize. VEGFR3 is a similar receptor but is proteolytically cleaved during synthesis, and held together with a disulfine bond between IgG 4 and 5. The coreceptors NP1 and NP2 interact with the VEGF receptors to aid signaling, intracellular sorting, and recycling to the membrane. VEGF‐B and PlGF both bind only to VEGFR1, VEGF‐A binds both VEGFR1 and VEGFR2 and VEGF‐C, and VEGF‐D bind to VEGFR3, but when proteolytically processed increase their affinity for VEGFR2.

Figure 2. Splicing of the VEGF‐A gene. The eight exons are differentially spliced to form multiple isoforms in two primary families, the proangiogenic VEGF‐Axxx, which use the proximal splice site in exon 8, and the partial agonist VEGF‐Axxxb family, which can prevent VEGF‐Axxx‐mediated angiogenesis, but can signal to prevent cytotoxicity through partial activation of VEGFR2.

Figure 3. Coverage of endothelial fenestrations by glycocalyx. Induction of fenestrations has been shown by VEGF, and VEGF knockdown in the glomerulus reduces fenestrations in glomerular endothelial cells. The endothelial cells, including the fenestrations, are covered with a glycocalyx (imaged in (A) using electron tomography transmission electron microscopy) (9). (B) In diabetes the glycocalyx is lost, but can be restored by treatment with VEGF‐A165b (206).
 1.Ablonczy Z, Prakasam A, Fant J, Fauq A, Crosson C, Sambamurti K. Pigment epithelium‐derived factor maintains retinal pigment epithelium function by inhibiting vascular endothelial growth factor‐R2 signaling through gamma‐secretase. J Biol Chem 284: 30177‐30186, 2009.
 2.Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, Nguyen HV, Aiello LM, Ferrara N, King GL. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331: 1480‐1487, 1994.
 3.Akkoyun I, Karabay G, Haberal N, Dagdeviren A, Yilmaz G, Oto S, Erkanli L, Akova YA. Structural consequences after intravitreal bevacizumab injection without increasing apoptotic cell death in a retinopathy of prematurity mouse model. Acta Ophthalmol 90(6): 564‐570, 2010.
 4.Alavi A, Hood JD, Frausto R, Stupack DG, Cheresh DA. Role of Raf in vascular protection from distinct apoptotic stimuli. Science 301: 94‐96, 2003.
 5.Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1: 1024‐1028, 1995.
 6.Amin EM, Oltean S, Hua J, Gammons MV, Hamdollah‐Zadeh M, Welsh GI, Cheung MK, Ni L, Kase S, Rennel ES, Symonds KE, Nowak DG, Royer‐Pokora B, Saleem MA, Hagiwara M, Schumacher VA, Harper SJ, Hinton DR, Bates DO, Ladomery MR. WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing. Cancer Cell 20: 768‐780, 2011.
 7.Arany Z, Foo SY, Ma Y, Ruas JL, Bommi‐Reddy A, Girnun G, Cooper M, Laznik D, Chinsomboon J, Rangwala SM, Baek KH, Rosenzweig A, Spiegelman BM. HIF‐independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC‐1alpha. Nature 451: 1008‐1012, 2008.
 8.Arcondeguy T, Lacazette E, Millevoi S, Prats H, Touriol C. VEGF‐A mRNA processing, stability and translation: A paradigm for intricate regulation of gene expression at the post‐transcriptional level. Nucleic Acids Res 41: 7997‐8010, 2013.
 9.Arkill KP, Qvortrup K, Starborg T, Mantell JM, Knupp C, Michel CC, Harper SJ, Salmon AH, Squire JM, Bates DO, Neal CR. Resolution of the three dimensional structure of components of the glomerular filtration barrier. BMC Nephrol 15: 24, 2014.
 10.Asanuma K, Mundel P. The role of podocytes in glomerular pathobiology. Clin Exp Nephrol 7: 255‐259, 2003.
 11.Atkins GB, Jain MK. Role of Kruppel‐like transcription factors in endothelial biology. Circ Res 100: 1686‐1695, 2007.
 12.Avci B, Avci R, Inan UU, Kaderli B. Comparative evaluation of apoptotic activity in photoreceptor cells after intravitreal injection of bevacizumab and pegaptanib sodium in rabbits. Invest Ophthalmol Vis Sci 50: 3438‐3446, 2009.
 13.Avraham‐Davidi I, Yona S, Grunewald M, Landsman L, Cochain C, Silvestre JS, Mizrahi H, Faroja M, Strauss‐Ayali D, Mack M, Jung S, Keshet E, Grunewald M, Avraham I, Dor Y, Bachar‐Lustig E, Itin A, Jung S, Chimenti S, Landsman L, Abramovitch R, Keshet E. On‐site education of VEGF‐recruited monocytes improves their performance as angiogenic and arteriogenic accessory cells VEGF‐induced adult neovascularization: recruitment, retention, and role of accessory cells. J Exp Med 210: 2611‐2625, 2013.
 14.Azzouz M, Ralph GS, Storkebaum E, Walmsley LE, Mitrophanous KA, Kingsman SM, Carmeliet P, Mazarakis ND. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429: 413‐417, 2004.
 15.Bailey E, Harper SJ, Pringle JH, Baker F, Furness PN, Salant DJ, Feehally J. Visceral glomerular epithelial cell DNA synthesis in experimental and human membranous disease. Exp Nephrol 6: 352‐358, 1998.
 16.Ballermann BJ. Glomerular endothelial cell differentiation. Kidney Int 67: 1668‐1671, 2005.
 17.Ballmer‐Hofer K, Andersson AE, Ratcliffe LE, Berger P. Neuropilin‐1 promotes VEGFR‐2 trafficking through Rab11 vesicles thereby specifying signal output. Blood 118(3): 816‐826, 2011.
 18.Barleon B, Sozzani S, Zhou D, Weich HA, Mantovani A, Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt‐1. Blood 87: 3336‐3343, 1996.
 19.Barratt SL, Blythe T, Jarrett C, Ourradi K, Shelley‐Fraser G, Day MJ, Qiu Y, Harper S, Maher TM, Oltean S, Hames T, Scotton C, Welsh GI, Bates DO, Millar AB. Differential expression of VEGF‐Axxx isoforms is critical for development of pulmonary fibrosis. Am J Respir Crit Care Med 196(4): 479‐493, 2017.
 20.Bates DO, Cui TG, Doughty JM, Winkler M, Sugiono M, Shields JD, Peat D, Gillatt D, Harper SJ. VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down‐regulated in renal cell carcinoma. Cancer Res 62: 4123‐4131, 2002.
 21.Bauer AT, Suckau J, Frank K, Desch A, Goertz L, Wagner AH, Hecker M, Goerge T, Umansky L, Beckhove P, Utikal J, Gorzelanny C, Diaz‐Valdes N, Umansky V, Schneider SW. von Willebrand factor fibers promote cancer‐associated platelet aggregation in malignant melanoma of mice and humans. Blood 125: 3153‐3163, 2015.
 22.Baum O, Da Silva‐Azevedo L, Willerding G, Wockel A, Planitzer G, Gossrau R, Pries AR, Zakrzewicz A. Endothelial NOS is main mediator for shear stress‐dependent angiogenesis in skeletal muscle after prazosin administration. Am J Physiol Heart Circ Physiol 287: H2300‐H2308, 2004.
 23.Baumwell S, Karumanchi SA. Pre‐eclampsia: Clinical manifestations and molecular mechanisms. Nephron Clin Pract 106: c72‐c81, 2007.
 24.Beazley‐Long N, Hua J, Jehle T, Hulse RP, Dersch R, Lehrling C, Bevan H, Qiu Y, Lagreze WA, Wynick D, Churchill AJ, Kehoe P, Harper SJ, Bates DO, Donaldson LF. VEGF‐A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro. Am J Pathol 183: 918‐929, 2013.
 25.Becker BF, Chappell D, Bruegger D, Annecke T, Jacob M. Therapeutic strategies targeting the endothelial glycocalyx: Acute deficits, but great potential. Cardiovasc Res 87: 300‐310, 2010.
 26.Berse B, Brown LF, Van de Water L, Dvorak HF, Senger DR. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 3: 211‐220, 1992.
 27.Bevan HS, van den Akker NM, Qiu Y, Polman JA, Foster RR, Yem J, Nishikawa A, Satchell SC, Harper SJ, Gittenberger‐de Groot AC, Bates DO. The alternatively spliced anti‐angiogenic family of VEGF isoforms VEGF(xxx)b in human kidney development. Nephron Physiol 110: p57‐p67, 2008.
 28.Bhandari V, Choo‐Wing R, Chapoval SP, Lee CG, Tang C, Kim YK, Ma B, Baluk P, Lin MI, McDonald DM, Homer RJ, Sessa WC, Elias JA. Essential role of nitric oxide in VEGF‐induced, asthma‐like angiogenic, inflammatory, mucus, and physiologic responses in the lung. Proc Natl Acad Sci U S A 103: 11021‐11026, 2006.
 29.Bonner JS, Lantier L, Hasenour CM, James FD, Bracy DP, Wasserman DH. Muscle‐specific vascular endothelial growth factor deletion induces muscle capillary rarefaction creating muscle insulin resistance. Diabetes 62: 572‐580, 2013.
 30.Breier G, Albrecht U, Sterrer S, Risau W. Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development 114: 521‐532, 1992.
 31.Brockington A, Wharton SB, Fernando M, Gelsthorpe CH, Baxter L, Ince PG, Lewis CE, Shaw PJ. Expression of vascular endothelial growth factor and its receptors in the central nervous system in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 65: 26‐36, 2006.
 32.Brockington A, Wokke B, Nixon H, Hartley J, Shaw PJ. Screening of the transcriptional regulatory regions of vascular endothelial growth factor receptor 2 (VEGFR2) in amyotrophic lateral sclerosis. BMC Med Genet 8: 23, 2007.
 33.Brown KR, England KM, Goss KL, Snyder JM, Acarregui MJ. VEGF induces airway epithelial cell proliferation in human fetal lung in vitro. Am J Physiol Lung Cell Mol Physiol 281: L1001‐L1010, 2001.
 34.Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Senger DR, Dvorak HF. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 53: 4727‐4735, 1993.
 35.Brown LF, Berse B, Tognazzi K, Manseau EJ, Van de Water L, Senger DR, Dvorak HF, Rosen S. Vascular permeability factor mRNA and protein expression in human kidney. Kidney Int 42: 1457‐1461, 1992.
 36.Cai J, Ahmad S, Jiang WG, Huang J, Kontos CD, Boulton M, Ahmed A. Activation of vascular endothelial growth factor receptor‐1 sustains angiogenesis and Bcl‐2 expression via the phosphatidylinositol 3‐kinase pathway in endothelial cells. Diabetes 52: 2959‐2968, 2003.
 37.Cai WJ, Kocsis E, Luo X, Schaper W, Schaper J. Expression of endothelial nitric oxide synthase in the vascular wall during arteriogenesis. Mol Cell Biochem 264: 193‐200, 2004.
 38.Cao L, Jiao X, Zuzga DS, Liu Y, Fong DM, Young D, During MJ. VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 36: 827‐835, 2004.
 39.Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J. Comparative evaluation of FGF‐2‐, VEGF‐A‐, and VEGF‐C‐induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability. Circ Res 94: 664‐670, 2004.
 40.Castle‐Miller J, Bates DO, Tortonese DJ. Mechanisms regulating angiogenesis underlie seasonal control of pituitary function. Proc Natl Acad Sci U S A 114: E2514‐E2523, 2017.
 41.Cebe Suarez S, Pieren M, Cariolato L, Arn S, Hoffmann U, Bogucki A, Manlius C, Wood J, Ballmer‐Hofer K. A VEGF‐A splice variant defective for heparan sulfate and neuropilin‐1 binding shows attenuated signaling through VEGFR‐2. Cell Mol Life Sci 63: 2067‐2077, 2006.
 42.Chattopadhyay M, Krisky D, Wolfe D, Glorioso JC, Mata M, Fink DJ. HSV‐mediated gene transfer of vascular endothelial growth factor to dorsal root ganglia prevents diabetic neuropathy. Gene Ther 12: 1377‐1384, 2005.
 43.Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 6: 465‐477, 2009.
 44.Christian HC, Imirtziadis L, Tortonese D. Ultrastructural changes in lactotrophs and folliculo‐stellate cells in the ovine pituitary during the annual reproductive cycle. J Neuroendocrinol 27: 277‐284, 2015.
 45.Clark‐Raymond A, Halaris A. VEGF and depression: A comprehensive assessment of clinical data. J Psychiatr Res 47: 1080‐1087, 2013.
 46.Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, Plaisance S, Dor Y, Keshet E, Lupu F, Nemery B, Dewerchin M, Van Veldhoven P, Plate K, Moons L, Collen D, Carmeliet P. Loss of HIF‐2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med 8: 702‐710, 2002.
 47.Constantinescu AA, Vink H, Spaan JA. Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface. Arterioscler Thromb Vasc Biol 23: 1541‐1547, 2003.
 48.Cosgrove GP, Brown KK, Schiemann WP, Serls AE, Parr JE, Geraci MW, Schwarz MI, Cool CD, Worthen GS. Pigment epithelium‐derived factor in idiopathic pulmonary fibrosis: A role in aberrant angiogenesis. Am J Respir Crit Care Med 170: 242‐251, 2004.
 49.Cui TG, Foster RR, Saleem MA, Mathieson PW, Gillatt DA, Bates DO, Harper SJ. Differentiated human podocytes endogenously express an inhibitory isoform of vascular endothelial growth factor (VEGF165b) mRNA and protein. Am J Physiol Renal Physiol 25: 25, 2003.
 50.Dane MJ, van den Berg BM, Avramut MC, Faas FG, van der Vlag J, Rops AL, Ravelli RB, Koster BJ, van Zonneveld AJ, Vink H, Rabelink TJ. Glomerular endothelial surface layer acts as a barrier against albumin filtration. Am J Pathol 182: 1532‐1540, 2013.
 51.Daniel PM, Prichard MM. The vascular arrangements of the pituitary gland. Q J Exp Physiol Cogn Med Sci 42: 237‐248, 1957.
 52.De Bock K, Georgiadou M, Carmeliet P. Role of endothelial cell metabolism in vessel sprouting. Cell Metab 18: 634‐647, 2013.
 53.De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, Quaegebeur A, Ghesquiere B, Cauwenberghs S, Eelen G, Phng LK, Betz I, Tembuyser B, Brepoels K, Welti J, Geudens I, Segura I, Cruys B, Bifari F, Decimo I, Blanco R, Wyns S, Vangindertael J, Rocha S, Collins RT, Munck S, Daelemans D, Imamura H, Devlieger R, Rider M, Van Veldhoven PP, Schuit F, Bartrons R, Hofkens J, Fraisl P, Telang S, Deberardinis RJ, Schoonjans L, Vinckier S, Chesney J, Gerhardt H, Dewerchin M, Carmeliet P. Role of PFKFB3‐driven glycolysis in vessel sprouting. Cell 154: 651‐663, 2013.
 54.De Paepe ME, Greco D, Mao Q. Angiogenesis‐related gene expression profiling in ventilated preterm human lungs. Exp Lung Res 36: 399‐410, 2010. Reviers MM, Ravault JP, Tillet Y, Pelletier J. Melatonin binding sites in the sheep pars tuberalis. Neurosci Lett 100: 89‐93, 1989.
 56.De Rossi P, Harde E, Dupuis JP, Martin L, Chounlamountri N, Bardin M, Watrin C, Benetollo C, Pernet‐Gallay K, Luhmann HJ, Honnorat J, Malleret G, Groc L, Acker‐Palmer A, Salin PA, Meissirel C. A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear‐related behavior. Mol Psychiatry 21: 1768‐1780, 2016. Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N, Williams LT. The fms‐like tyrosine kinase, a receptor for vascular endothelial growth factor. Science 255: 989‐991, 1992.
 58.Del Bo R, Scarlato M, Ghezzi S, Martinelli‐Boneschi F, Corti S, Locatelli F, Santoro D, Prelle A, Briani C, Nardini M, Siciliano G, Mancuso M, Murri L, Bresolin N, Comi GP. Absence of angiogenic genes modification in Italian ALS patients. Neurobiol Aging 29: 314‐316, 2008.
 59.dela Paz NG, Walshe TE, Leach LL, Saint‐Geniez M, D'Amore PA. Role of shear‐stress‐induced VEGF expression in endothelial cell survival. J Cell Sci 125: 831‐843, 2012.
 60.Doddaballapur A, Michalik KM, Manavski Y, Lucas T, Houtkooper RH, You X, Chen W, Zeiher AM, Potente M, Dimmeler S, Boon RA. Laminar shear stress inhibits endothelial cell metabolism via KLF2‐mediated repression of PFKFB3. Arterioscler Thromb Vasc Biol 35: 137‐145, 2015.
 61.Dokter M, von Bohlen und Halbach O. Neurogenesis within the adult hippocampus under physiological conditions and in depression. Neural Regen Res 7: 552‐559, 2012.
 62.Domigan CK, Warren CM, Antanesian V, Happel K, Ziyad S, Lee S, Krall A, Duan L, Torres‐Collado AX, Castellani LW, Elashoff D, Christofk HR, van der Bliek AM, Potente M, Iruela‐Arispe ML. Autocrine VEGF maintains endothelial survival through regulation of metabolism and autophagy. J Cell Sci 128: 2236‐2248, 2015.
 63.Drumond MC, Deen WM. Structural determinants of glomerular hydraulic permeability. Am J Physiol 266: F1‐F12, 1994.
 64.During MJ, Cao L. VEGF, a mediator of the effect of experience on hippocampal neurogenesis. Curr Alzheimer Res 3: 29‐33, 2006.
 65.Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146: 1029‐1039, 1995.
 66.Ebina M, Shimizukawa M, Shibata N, Kimura Y, Suzuki T, Endo M, Sasano H, Kondo T, Nukiwa T. Heterogeneous increase in CD34‐positive alveolar capillaries in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 169: 1203‐1208, 2004.
 67.Eelen G, de Zeeuw P, Simons M, Carmeliet P. Endothelial cell metabolism in normal and diseased vasculature. Circ Res 116: 1231‐1244, 2015.
 68.Egginton S, Hudlicka O. Early changes in performance, blood flow and capillary fine structure in rat fast muscles induced by electrical stimulation. J Physiol (Lond) 515 (Pt 1): 265‐275, 1999.
 69.Elias I, Franckhauser S, Ferre T, Vila L, Tafuro S, Munoz S, Roca C, Ramos D, Pujol A, Riu E, Ruberte J, Bosch F. Adipose tissue overexpression of vascular endothelial growth factor protects against diet‐induced obesity and insulin resistance. Diabetes 61: 1801‐1813, 2012.
 70.Elmasri H, Karaaslan C, Teper Y, Ghelfi E, Weng M, Ince TA, Kozakewich H, Bischoff J, Cataltepe S. Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells. Faseb J 23: 3865‐3873, 2009.
 71.Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE, Quaggin SE. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 358: 1129‐1136, 2008.
 72.Eremina V, Quaggin SE. The role of VEGF‐A in glomerular development and function. Curr Opin Nephrol Hypertens 13: 9‐15, 2004.
 73.Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE. Glomerular‐specific alterations of VEGF‐A expression lead to distinct congenital and acquired renal diseases. J Clin Invest 111: 707‐716, 2003.
 74.Esser S, Wolburg K, Wolburg H, Breier G, Kurzchalia T, Risau W. Vascular endothelial growth factor induces endothelial fenestrations in vitro. J Cell Biol 140: 947‐959, 1998.
 75.Eubank TD, Roberts R, Galloway M, Wang Y, Cohn DE, Marsh CB. GM‐CSF induces expression of soluble VEGF receptor‐1 from human monocytes and inhibits angiogenesis in mice. Immunity 21: 831‐842, 2004.
 76.Fabel K, Fabel K, Tam B, Kaufer D, Baiker A, Simmons N, Kuo CJ, Palmer TD. VEGF is necessary for exercise‐induced adult hippocampal neurogenesis. Eur J Neurosci 18: 2803‐2812, 2003.
 77.Fava RA, Olsen NJ, Spencer‐Green G, Yeo KT, Yeo TK, Berse B, Jackman RW, Senger DR, Dvorak HF, Brown LF. Vascular permeability factor/endothelial growth factor (VPF/VEGF): Accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med 180: 341‐346, 1994.
 78.Fearnley GW, Odell AF, Latham AM, Mughal NA, Bruns AF, Burgoyne NJ, Homer‐Vanniasinkam S, Zachary IC, Hollstein MC, Wheatcroft SB, Ponnambalam S. VEGF‐A isoforms differentially regulate ATF‐2‐dependent VCAM‐1 gene expression and endothelial‐leukocyte interactions. Mol Biol Cell 25: 2509‐2521, 2014.
 79.Fehrenbach H, Kasper M, Haase M, Schuh D, Muller M. Differential immunolocalization of VEGF in rat and human adult lung, and in experimental rat lung fibrosis: Light, fluorescence, and electron microscopy. Anat Rec 254: 61‐73, 1999.
 80.Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P. Anti‐PlGF inhibits growth of VEGF(R)‐inhibitor‐resistant tumors without affecting healthy vessels. Cell 131: 463‐475, 2007.
 81.Foster RR, Armstrong L, Baker S, Wong DW, Wylie EC, Ramnath R, Jenkins R, Singh A, Steadman R, Welsh GI, Mathieson PW, Satchell SC. Glycosaminoglycan regulation by VEGFA and VEGFC of the glomerular microvascular endothelial cell glycocalyx in vitro. Am J Pathol 183: 604‐616, 2013.
 82.Foster RR, Hole R, Anderson K, Satchell SC, Coward RJ, Mathieson PW, Gillatt DA, Saleem MA, Bates DO, Harper SJ. Functional evidence that vascular endothelial growth factor may act as an autocrine factor on human podocytes. Am J Physiol Renal Physiol 284: F1263‐F1273, 2003.
 83.Foster RR, Saleem MA, Mathieson PW, Bates DO, Harper SJ. Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes. Am J Physiol Renal Physiol 31: 31, 2004.
 84.Foster RR, Slater SC, Seckley J, Kerjaschki D, Bates DO, Mathieson PW, Satchell SC. Vascular endothelial growth factor‐C, a potential paracrine regulator of glomerular permeability, increases glomerular endothelial cell monolayer integrity and intracellular calcium. Am J Pathol 173: 938‐948, 2008.
 85.Fufaa GD, Weil EJ, Lemley KV, Knowler WC, Brosius FC, III, Yee B, Mauer M, Nelson RG. Structural predictors of loss of renal function in American Indians with type 2 diabetes. Clin J Am Soc Nephrol 11: 254‐261, 2016.
 86.Furuhashi M, Hotamisligil GS. Fatty acid‐binding proteins: Role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 7: 489‐503, 2008.
 87.Garmy‐Susini B, Avraamides CJ, Desgrosellier JS, Schmid MC, Foubert P, Ellies LG, Lowy AM, Blair SL, Vandenberg SR, Datnow B, Wang HY, Cheresh DA, Varner J. PI3Kalpha activates integrin alpha4beta1 to establish a metastatic niche in lymph nodes. Proc Natl Acad Sci U S A 110: 9042‐9047, 2013.
 88.Garmy‐Susini B, Avraamides CJ, Schmid MC, Foubert P, Ellies LG, Barnes L, Feral C, Papayannopoulou T, Lowy A, Blair SL, Cheresh D, Ginsberg M, Varner JA. Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Res 70: 3042‐3051, 2010.
 89.Gerber HP, Dixit V, Ferrara N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl‐2 and A1 in vascular endothelial cells. J Biol Chem 273: 13313‐13316, 1998.
 90.Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, Wright BD, Radtke F, Aguet M, Ferrara N. VEGF is required for growth and survival in neonatal mice. Development 126: 1149‐1159, 1999.
 91.Gerber HP, McMurtrey A, Kowalski J, Yan M, Keyt BA, Dixit V, Ferrara N. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′‐kinase/Akt signal transduction pathway. Requirement for Flk‐1/KDR activation. J Biol Chem 273: 30336‐30343, 1998.
 92.Goettsch W, Gryczka C, Korff T, Ernst E, Goettsch C, Seebach J, Schnittler HJ, Augustin HG, Morawietz H. Flow‐dependent regulation of angiopoietin‐2. J Cell Physiol 214: 491‐503, 2008.
 93.Green JD. The comparative anatomy of the hypophysis, with special reference to its blood supply and innervation. Am J Anat 88: 225‐311, 1951.
 94.Green JD, Harris GW. The neurovascular link between the neurohypophysis and adenohypophysis. J Endocrinol 5: 136‐146, 1947.
 95.Greenberg JM, Thompson FY, Brooks SK, Shannon JM, McCormick‐Shannon K, Cameron JE, Mallory BP, Akeson AL. Mesenchymal expression of vascular endothelial growth factors D and A defines vascular patterning in developing lung. Dev Dyn 224: 144‐153, 2002.
 96.Grosios K, Wood J, Esser R, Raychaudhuri A, Dawson J. Angiogenesis inhibition by the novel VEGF receptor tyrosine kinase inhibitor, PTK787/ZK222584, causes significant anti‐arthritic effects in models of rheumatoid arthritis. Inflamm Res 53: 133‐142, 2004.
 97.Grunewald FS, Prota AE, Giese A, Ballmer‐Hofer K. Structure‐function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling. Biochim Biophys Acta 1804: 567‐580, 2010.
 98.Grunewald M, Avraham I, Dor Y, Bachar‐Lustig E, Itin A, Jung S, Chimenti S, Landsman L, Abramovitch R, Keshet E. VEGF‐induced adult neovascularization: Recruitment, retention, and role of accessory cells. Cell 124: 175‐189, 2006.
 99.Hagberg C, Mehlem A, Falkevall A, Muhl L, Eriksson U. Endothelial fatty acid transport: Role of vascular endothelial growth factor B. Physiology 28: 125‐134, 2013.
 100.Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, van Meeteren LA, Samen E, Lu L, Vanwildemeersch M, Klar J, Genove G, Pietras K, Stone‐Elander S, Claesson‐Welsh L, Yla‐Herttuala S, Lindahl P, Eriksson U. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 464: 917‐921, 2010.
 101.Hagberg CE, Mehlem A, Falkevall A, Muhl L, Fam BC, Ortsater H, Scotney P, Nyqvist D, Samen E, Lu L, Stone‐Elander S, Proietto J, Andrikopoulos S, Sjoholm A, Nash A, Eriksson U. Targeting VEGF‐B as a novel treatment for insulin resistance and type 2 diabetes. Nature 490: 426‐430, 2012.
 102.Harper SJ, Bates DO. VEGF‐A splicing: The key to anti‐angiogenic therapeutics? Nat Rev Cancer 8: 880‐887, 2008.
 103.Heiduschka P, Julien S, Hofmeister S, Bartz‐Schmidt KU, Schraermeyer U. Bevacizumab (avastin) does not harm retinal function after intravitreal injection as shown by electroretinography in adult mice. Retina 28: 46‐55, 2008.
 104.Hillman NJ, Whittles CE, Pocock TM, Williams B, Bates DO. Differential effects of vascular endothelial growth factor‐C and placental growth factor‐1 on the hydraulic conductivity of frog mesenteric capillaries. J Vasc Res 38: 176‐186, 2001.
 105.Hirschhaeuser F, Sattler UG, Mueller‐Klieser W. Lactate: A metabolic key player in cancer. Cancer Res 71: 6921‐6925, 2011.
 106.Hjalmarsson C, Johansson BR, Haraldsson B. Electron microscopic evaluation of the endothelial surface layer of glomerular capillaries. Microvasc Res 67: 9‐17, 2004.
 107.Hohenstein B, Colin M, Foellmer C, Amann KU, Brekken RA, Daniel C, Hugo CP. Autocrine VEGF‐VEGF‐R loop on podocytes during glomerulonephritis in humans. Nephrol Dial Transplant 25: 3170‐3180, 2010.
 108.Hohman TJ, Bell SP, Jefferson AL, Alzheimer's Disease Neuroimaging Initiative. The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: Exploring interactions with biomarkers of Alzheimer disease. JAMA Neurol 72: 520‐529, 2015.
 109.Hoier B, Prats C, Qvortrup K, Pilegaard H, Bangsbo J, Hellsten Y. Subcellular localization and mechanism of secretion of vascular endothelial growth factor in human skeletal muscle. Faseb J 27: 3496‐3504, 2013.
 110.Houck KA, Leung DW, Rowland AM, Winer J, Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem 267: 26031‐26037, 1992.
 111.Houssay BA, Biasotti A, Sammartino R. CR Soc Biol, Paris 120: 725, 1935.
 112.Hua J, Spee C, Kase S, Rennel ES, Magnussen AL, Qiu Y, Varey A, Dhayade S, Churchill AJ, Harper SJ, Bates DO, Hinton DR. Recombinant human VEGF165b inhibits experimental choroidal neovascularization. Invest Ophthalmol Vis Sci 51: 4282‐4288, 2010.
 113.Huang H, Langenkamp E, Georganaki M, Loskog A, Fuchs PF, Dieterich LC, Kreuger J, Dimberg A. VEGF suppresses T‐lymphocyte infiltration in the tumor microenvironment through inhibition of NF‐kappaB‐induced endothelial activation. Faseb J 29: 227‐238, 2015.
 114.Hudson N, Powner MB, Sarker MH, Burgoyne T, Campbell M, Ockrim ZK, Martinelli R, Futter CE, Grant MB, Fraser PA, Shima DT, Greenwood J, Turowski P. Differential apicobasal VEGF signaling at vascular blood‐neural barriers. Dev Cell 30: 541‐552, 2014.
 115.Hulse R, Wynick D, Donaldson L. Intact cutaneous C fibre afferent properties in mechanical and cold neuropathic allodynia. Eur J Pain 14: 565, 2010.
 116.Hulse RP, Beazley‐Long N, Hua J, Kennedy H, Prager J, Bevan H, Qiu Y, Fernandes ES, Gammons MV, Ballmer‐Hofer K, Gittenberger de Groot AC, Churchill AJ, Harper SJ, Brain SD, Bates DO, Donaldson LF. Regulation of alternative VEGF‐A mRNA splicing is a therapeutic target for analgesia. Neurobiol Dis 71: 245‐259, 2014.
 117.Hulse RP, Beazley‐Long N, Ved N, Bestall SM, Riaz H, Singhal P, Ballmer Hofer K, Harper SJ, Bates D, Donaldson LF. Vascular endothelial growth factor‐A165b prevents diabetic neuropathic pain and sensory neuronal degeneration. Clin Sci 129: 741‐756, 2015.
 118.Hulse RP, Drake RA, Bates DO, Donaldson LF. The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain. Neurobiol Dis 96: 186‐200, 2016.
 119.Ichimura K, Stan RV, Kurihara H, Sakai T. Glomerular endothelial cells form diaphragms during development and pathologic conditions. J Am Soc Nephrol 19: 1463‐1471, 2008.
 120.Inan UU, Avci B, Kusbeci T, Kaderli B, Avci R, Temel SG. Preclinical safety evaluation of intravitreal injection of full‐length humanized vascular endothelial growth factor antibody in rabbit eyes. Invest Ophthalmol Vis Sci 48: 1773‐1781, 2007.
 121.Ishida A, Murray J, Saito Y, Kanthou C, Benzakour O, Shibuya M, Wijelath ES. Expression of vascular endothelial growth factor receptors in smooth muscle cells. J Cell Physiol 188: 359‐368, 2001.
 122.Jabbour HN, Boddy SC, Lincoln GA. Pattern and localisation of expression of vascular endothelial growth factor and its receptor flt‐1 in the ovine pituitary gland: Expression is independent of hypothalamic control. Mol Cell Endocrinol 134: 91‐100, 1997.
 123.Janer J, Andersson S, Haglund C, Karikoski R, Lassus P. Placental growth factor and vascular endothelial growth factor receptor‐2 in human lung development. Pediatrics 122: 340‐346, 2008.
 124.Janer J, Lassus P, Haglund C, Paavonen K, Alitalo K, Andersson S. Pulmonary vascular endothelial growth factor‐C in development and lung injury in preterm infants. Am J Respir Crit Care Med 174: 326‐330, 2006.
 125.Jia H, Bagherzadeh A, Bicknell R, Duchen MR, Liu D, Zachary I. Vascular endothelial growth factor (VEGF)‐D and VEGF‐A differentially regulate KDR‐mediated signaling and biological function in vascular endothelial cells. J Biol Chem 279: 36148‐36157, 2004.
 126.Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A 99: 11946‐11950, 2002.
 127.Jin KL, Mao XO, Greenberg DA. Vascular endothelial growth factor rescues HN33 neural cells from death induced by serum withdrawal. J Mol Neurosci 14: 197‐203, 2000.
 128.Jin KL, Mao XO, Nagayama T, Goldsmith PC, Greenberg DA. Induction of vascular endothelial growth factor and hypoxia‐inducible factor‐1alpha by global ischemia in rat brain. Neuroscience 99: 577‐585, 2000.
 129.Joory KD, Levick JR, Mortimer PS, Bates DO. Vascular endothelial growth factor‐C (VEGF‐C) expression in normal human tissues. Lymphat Res Biol 4: 73‐82, 2006.
 130.Kaner RJ, Crystal RG. Compartmentalization of vascular endothelial growth factor to the epithelial surface of the human lung. Mol Med 7: 240‐246, 2001.
 131.Karpanen T, Bry M, Ollila HM, Seppanen‐Laakso T, Liimatta E, Leskinen H, Kivela R, Helkamaa T, Merentie M, Jeltsch M, Paavonen K, Andersson LC, Mervaala E, Hassinen IE, Yla‐Herttuala S, Oresic M, Alitalo K. Overexpression of vascular endothelial growth factor‐B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy. Circ Res 103: 1018‐1026, 2008.
 132.Kasahara Y, Tuder RM, Taraseviciene‐Stewart L, Le Cras TD, Abman S, Hirth PK, Waltenberger J, Voelkel NF. Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. J Clin Invest 106: 1311‐1319, 2000.
 133.Kaur C, Foulds WS, Ling EA. Blood‐retinal barrier in hypoxic ischaemic conditions: Basic concepts, clinical features and management. Prog Retin Eye Res 27: 622‐647, 2008.
 134.Kawamura H, Li X, Harper SJ, Bates DO, Claesson‐Welsh L. Vascular endothelial growth factor (VEGF)‐A165b is a weak in vitro agonist for VEGF receptor‐2 due to lack of coreceptor binding and deficient regulation of kinase activity. Cancer Res 68: 4683‐4692, 2008.
 135.Kearns MT, Dalal S, Horstmann SA, Richens TR, Tanaka T, Doe JM, Boe DM, Voelkel NF, Taraseviciene‐Stewart L, Janssen WJ, Lee CG, Elias JA, Bratton D, Tuder RM, Henson PM, Vandivier RW. Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells. Am J Physiol Lung Cell Mol Physiol 302: L711‐L718, 2012.
 136.Kent DL. Age‐related macular degeneration: Beyond anti‐angiogenesis. Mol Vis 20: 46‐55, 2014.
 137.Kikuchi R, Nakamura K, MacLauchlan S, Ngo DT, Shimizu I, Fuster JJ, Katanasaka Y, Yoshida S, Qiu Y, Yamaguchi TP, Matsushita T, Murohara T, Gokce N, Bates DO, Hamburg NM, Walsh K. An antiangiogenic isoform of VEGF‐A contributes to impaired vascularization in peripheral artery disease. Nat Med 20(12): 1464‐1471, 2014.
 138.Kikuchi R, Nakamura K, MacLauchlan S, Ngo DT, Shimizu I, Fuster JJ, Katanasaka Y, Yoshida S, Qiu Y, Yamaguchi TP, Matsushita T, Murohara T, Gokce N, Bates DO, Hamburg NM, Walsh K. An antiangiogenic isoform of VEGF‐A contributes to impaired vascularization in peripheral artery disease. Nat Med 20: 1464‐1471, 2014.
 139.Kim JH, Kim C, Lee BJ, Yu YS, Park KH, Kim KW. Absence of intravitreal bevacizumab‐induced neuronal toxicity in the retina. Neurotoxicology 29: 1131‐1135, 2008.
 140.Kim S, Kim YJ, Kim NR, Chin HS. Effects of bevacizumab on Bcl‐2 expression and apoptosis in retinal pigment epithelial cells under oxidative stress. Korean J Ophthalmol 29: 424‐432, 2015.
 141.Kirby ED, Kuwahara AA, Messer RL, Wyss‐Coray T. Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF. Proc Natl Acad Sci U S A 112: 4128‐4133, 2015.
 142.Kishuku M, Nishioka Y, Abe S, Kishi J, Ogino H, Aono Y, Azuma M, Kinoshita K, Batmunkh R, Makino H, Ranjan P, Minakuchi K, Sone S. Expression of soluble vascular endothelial growth factor receptor‐1 in human monocyte‐derived mature dendritic cells contributes to their antiangiogenic property. J Immunol 183: 8176‐8185, 2009.
 143.Kivela R, Bry M, Robciuc MR, Rasanen M, Taavitsainen M, Silvola JM, Saraste A, Hulmi JJ, Anisimov A, Mayranpaa MI, Lindeman JH, Eklund L, Hellberg S, Hlushchuk R, Zhuang ZW, Simons M, Djonov V, Knuuti J, Mervaala E, Alitalo K. VEGF‐B‐induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart. EMBO Mol Med 6: 307‐321, 2014.
 144.Knapp AE, Goldberg D, Delavar H, Trisko BM, Tang K, Hogan MC, Wagner PD, Breen EC. Skeletal myofiber VEGF regulates contraction‐induced perfusion and exercise capacity but not muscle capillarity in adult mice. Am J Physiol Regul Integr Comp Physiol 311: R192‐R199, 2016.
 145.Ku DD, Zaleski JK, Liu S, Brock TA. Vascular endothelial growth factor induces EDRF‐dependent relaxation in coronary arteries. Am J Physiol 265: H586‐H592, 1993.
 146.Kuhn H, Kruger S, Hammerschmidt S, Wirtz H. High concentrations of vascular endothelial growth factor reduce stretch‐induced apoptosis of alveolar type II cells. Respirology 15: 343‐348, 2010.
 147.Kwak N, Okamoto N, Wood JM, Campochiaro PA. VEGF is major stimulator in model of choroidal neovascularization. Invest Ophthalmol Vis Sci 41: 3158‐3164, 2000.
 148.Lambrechts D, Storkebaum E, Morimoto M, Del‐Favero J, Desmet F, Marklund SL, Wyns S, Thijs V, Andersson J, van Marion I, Al‐Chalabi A, Bornes S, Musson R, Hansen V, Beckman L, Adolfsson R, Pall HS, Prats H, Vermeire S, Rutgeerts P, Katayama S, Awata T, Leigh N, Lang‐Lazdunski L, Dewerchin M, Shaw C, Moons L, Vlietinck R, Morrison KE, Robberecht W, Van Broeckhoven C, Collen D, Andersen PM, Carmeliet P. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet 34: 383‐394, 2003.
 149.Lang‐Lazdunski L, Matsushita K, Hirt L, Waeber C, Vonsattel JP, Moskowitz MA, Dietrich WD. Spinal cord ischemia. Development of a model in the mouse. Stroke 31: 208‐213, 2000.
 150.Langlet F, Levin BE, Luquet S, Mazzone M, Messina A, Dunn‐Meynell AA, Balland E, Lacombe A, Mazur D, Carmeliet P, Bouret SG, Prevot V, Dehouck B. Tanycytic VEGF‐A boosts blood‐hypothalamus barrier plasticity and access of metabolic signals to the arcuate nucleus in response to fasting. Cell Metab 17: 607‐617, 2013.
 151.Le Cras TD, Spitzmiller RE, Albertine KH, Greenberg JM, Whitsett JA, Akeson AL. VEGF causes pulmonary hemorrhage, hemosiderosis, and air space enlargement in neonatal mice. Am J Physiol Lung Cell Mol Physiol 287: L134‐L142, 2004.
 152.Lee DW, Miyasato LE, Clayton NS. Neurobiological bases of spatial learning in the natural environment: Neurogenesis and growth in the avian and mammalian hippocampus. Neuroreport 9: R15‐R27, 1998.
 153.Lee E, Son H. Adult hippocampal neurogenesis and related neurotrophic factors. BMB Rep 42: 239‐244, 2009.
 154.Lee S, Chen TT, Barber CL, Jordan MC, Murdock J, Desai S, Ferrara N, Nagy A, Roos KP, Iruela‐Arispe ML. Autocrine VEGF signaling is required for vascular homeostasis. Cell 130: 691‐703, 2007.
 155.Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246: 1306‐1309, 1989.
 156.Li M, Scott DE, Shandas R, Stenmark KR, Tan W. High pulsatility flow induces adhesion molecule and cytokine mRNA expression in distal pulmonary artery endothelial cells. Ann Biomed Eng 37: 1082‐1092, 2009.
 157.Licht T, Goshen I, Avital A, Kreisel T, Zubedat S, Eavri R, Segal M, Yirmiya R, Keshet E. Reversible modulations of neuronal plasticity by VEGF. Proc Natl Acad Sci U S A 108: 5081‐5086, 2011.
 158.Lieberwirth C, Pan Y, Liu Y, Zhang Z, Wang Z. Hippocampal adult neurogenesis: Its regulation and potential role in spatial learning and memory. Brain Res 1644: 127‐140, 2016.
 159.Lin J, Li G, Den X, Xu C, Liu S, Gao Y, Liu H, Zhang J, Li X, Liang S. VEGF and its receptor‐2 involved in neuropathic pain transmission mediated by P2X(2)(/)(3) receptor of primary sensory neurons. Brain Res Bull 83: 284‐291, 2010.
 160.Lincoln GA, Clarke IJ. Photoperiodically‐induced cycles in the secretion of prolactin in hypothalamo‐pituitary disconnected rams: evidence for translation of the melatonin signal in the pituitary gland. J Neuroendocrinol 6: 251‐260, 1994.
 161.Liu S, Xu C, Li G, Liu H, Xie J, Tu G, Peng H, Qiu S, Liang S. Vatalanib decrease the positive interaction of VEGF receptor‐2 and P2X2/3 receptor in chronic constriction injury rats. Neurochem Int 60: 565‐572, 2012.
 162.Lloyd PG, Prior BM, Li H, Yang HT, Terjung RL. VEGF receptor antagonism blocks arteriogenesis, but only partially inhibits angiogenesis, in skeletal muscle of exercise‐trained rats. Am J Physiol Heart & Circ 288: H759‐H768, 2005.
 163.Louissaint A, Jr., Rao S, Leventhal C, Goldman SA. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34: 945‐960, 2002.
 164.Lunn JS, Sakowski SA, Kim B, Rosenberg AA, Feldman EL. Vascular endothelial growth factor prevents G93A‐SOD1‐induced motor neuron degeneration. Dev Neurobiol 69: 871‐884, 2009.
 165.Magnussen AL, Rennel ES, Hua J, Bevan HS, Beazley Long N, Lehrling C, Gammons M, Floege J, Harper SJ, Agostini HT, Bates DO, Churchill AJ. VEGF‐A165b is cytoprotective and antiangiogenic in the retina. Invest Ophthalmol Vis Sci 51: 4273‐4281, 2010.
 166.Maharaj AS, D'Amore PA. Roles for VEGF in the adult. Microvasc Res 74: 100‐113, 2007.
 167.Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, Kauppinen R, Jackson DG, Kubo H, Nishikawa S, Yla‐Herttuala S, Alitalo K. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor‐3. Nat Med 7: 199‐205, 2001.
 168.Malykhina AP, Lei Q, Erickson CS, Epstein ML, Saban MR, Davis CA, Saban R. VEGF induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity. BMC Physiol 12: 15, 2012.
 169.Manetti M, Guiducci S, Romano E, Ceccarelli C, Bellando‐Randone S, Conforti ML, Ibba‐Manneschi L, Matucci‐Cerinic M. Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis. Circ Res 109:e14‐e26, 2011.
 170.Maniscalco WM, Watkins RH, D'Angio CT, Ryan RM. Hyperoxic injury decreases alveolar epithelial cell expression of vascular endothelial growth factor (VEGF) in neonatal rabbit lung. Am J Respir Cell Mol Biol 16: 557‐567, 1997.
 171.Marneros AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, Crouch RK, Olsen BR. Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol 167: 1451‐1459, 2005.
 172.Matsuoka A, Maeda O, Mizutani T, Nakano Y, Tsunoda N, Kikumori T, Goto H, Ando Y. Bevacizumab exacerbates paclitaxel‐induced neuropathy: A retrospective cohort study. PLoS One 11: e0168707, 2016.
 173.Matsuzaki H, Tamatani M, Yamaguchi A, Namikawa K, Kiyama H, Vitek MP, Mitsuda N, Tohyama M. Vascular endothelial growth factor rescues hippocampal neurons from glutamate‐induced toxicity: Signal transduction cascades. Faseb J 15: 1218‐1220, 2001.
 174.Medford AR, Douglas SK, Godinho SI, Uppington KM, Armstrong L, Gillespie KM, van Zyl B, Tetley TD, Ibrahim NB, Millar AB. Vascular endothelial growth factor (VEGF) isoform expression and activity in human and murine lung injury. Respir Res 10: 27, 2009.
 175.Medford AR, Ibrahim NB, Millar AB. Vascular endothelial growth factor receptor and coreceptor expression in human acute respiratory distress syndrome. J Crit Care 24: 236‐242, 2009.
 176.Medford AR, Millar AB. Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): Paradox or paradigm? Thorax 61: 621‐626, 2006.
 177.Merdzhanova G, Gout S, Keramidas M, Edmond V, Coll JL, Brambilla C, Brambilla E, Gazzeri S, Eymin B. The transcription factor E2F1 and the SR protein SC35 control the ratio of pro‐angiogenic versus antiangiogenic isoforms of vascular endothelial growth factor‐A to inhibit neovascularization in vivo. Oncogene 29: 5392‐5403, 2010.
 178.Milkiewicz M, Hudlicka O, Verhaeg J, Egginton S, Brown MD. Differential expression of Flk‐1 and Flt‐1 in rat skeletal muscle in response to chronic ischaemia: Favourable effect of muscle activity. Clin Sci (Lond) 105: 473‐482, 2003.
 179.Miner JH. Glomerular basement membrane composition and the filtration barrier. Pediatr Nephrol 26: 1413‐1417, 2011.
 180.Miyamoto K, Khosrof S, Bursell SE, Moromizato Y, Aiello LP, Ogura Y, Adamis AP. Vascular endothelial growth factor (VEGF)‐induced retinal vascular permeability is mediated by intercellular adhesion molecule‐1 (ICAM‐1). Am J Pathol 156: 1733‐1739, 2000.
 181.Monacci WT, Merrill MJ, Oldfield EH. Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol 264: C995‐C1002, 1993.
 182.Mortara L, Benest AV, Bates DO, Noonan DM. Can the co‐dependence of the immune system and angiogenesis facilitate pharmacological targeting of tumours? Curr Opin Pharmacol 35: 66‐74, 2017.
 183.Mukhopadhyay D, Knebelmann B, Cohen HT, Ananth S, Sukhatme VP. The von Hippel‐Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol Cell Biol 17: 5629‐5639, 1997.
 184.Mulder SF, Bertens D, Desar IM, Vissers KC, Mulders PF, Punt CJ, van Spronsen DJ, Langenhuijsen JF, Kessels RP, van Herpen CM. Impairment of cognitive functioning during Sunitinib or Sorafenib treatment in cancer patients: A cross sectional study. BMC Cancer 14: 219, 2014.
 185.Muller WA. The regulation of transendothelial migration: New knowledge and new questions. Cardiovasc Res 107: 310‐320, 2015.
 186.Mura M, Binnie M, Han B, Li C, Andrade CF, Shiozaki A, Zhang Y, Ferrara N, Hwang D, Waddell TK, Keshavjee S, Liu M. Functions of type II pneumocyte‐derived vascular endothelial growth factor in alveolar structure, acute inflammation, and vascular permeability. Am J Pathol 176: 1725‐1734, 2010.
 187.Mura M, Han B, Andrade CF, Seth R, Hwang D, Waddell TK, Keshavjee S, Liu M. The early responses of VEGF and its receptors during acute lung injury: implication of VEGF in alveolar epithelial cell survival. Critical care 10: R130, 2006.
 188.Murakami T, Arai M, Sunada Y, Nakamura A. VEGF 164 gene transfer by electroporation improves diabetic sensory neuropathy in mice. J Gene Med 8: 773‐781, 2006.
 189.Murrant CL, Sarelius IH. Coupling of muscle metabolism and muscle blood flow in capillary units during contraction. Acta Physiol Scand 168: 531‐541, 2000.
 190.Nadaud S, Philippe M, Arnal JF, Michel JB, Soubrier F. Sustained increase in aortic endothelial nitric oxide synthase expression in vivo in a model of chronic high blood flow. Circ Res 79: 857‐863, 1996.
 191.Neal CR, Crook H, Bell E, Harper SJ, Bates DO. Three‐dimensional reconstruction of glomeruli by electron microscopy reveals a distinct restrictive urinary subpodocyte space. J Am Soc Nephrol 16: 1223‐1235, 2005.
 192.Neal CR, Muston PR, Njegovan D, Verrill R, Harper SJ, Deen WM, Bates DO. Glomerular filtration into the subpodocyte space is highly restricted under physiological perfusion conditions. Am J Physiol Renal Physiol 293: F1787‐F1798, 2007.
 193.Nesic O, Sundberg LM, Herrera JJ, Mokkapati VU, Lee J, Narayana PA. Vascular endothelial growth factor and spinal cord injury pain. J Neurotrauma 27: 1793‐1803, 2010.
 194.Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. Faseb J 13: 9‐22, 1999.
 195.Nowak DG, Amin EM, Rennel ES, Hoareau‐Aveilla C, Gammons M, Damodoran G, Hagiwara M, Harper SJ, Woolard J, Ladomery MR, Bates DO. Regulation of vascular endothelial growth factor (VEGF) splicing from pro‐angiogenic to anti‐angiogenic isoforms: A novel therapeutic strategy for angiogenesis. J Biol Chem 285: 5532‐5540, 2010.
 196.Nowak DG, Woolard J, Amin EM, Konopatskaya O, Saleem MA, Churchill AJ, Ladomery MR, Harper SJ, Bates DO. Expression of pro‐ and anti‐angiogenic isoforms of VEGF is differentially regulated by known splicing and growth factors. J Cell Sci 121: 3487‐3495, 2008.
 197.Noy P, Sawasdichai A, Jayaraman PS, Gaston K. Protein kinase CK2 inactivates PRH/Hhex using multiple mechanisms to de‐repress VEGF‐signalling genes and promote cell survival. Nucleic Acids Res 40: 9008‐9020, 2012.
 198.Noy P, Williams H, Sawasdichai A, Gaston K, Jayaraman PS. PRH/Hhex controls cell survival through coordinate transcriptional regulation of vascular endothelial growth factor signaling. Mol Cell Biol 30: 2120‐2134, 2010.
 199.Obeidat M, Obeidat M, Ballermann BJ. Glomerular endothelium: A porous sieve and formidable barrier. Exp Cell Res 318: 964‐972, 2012.
 200.Oh DH, Kim BW, Choi M, Lee G, Choi JS, Hyeon S. Changes in vascular endothelial growth factor (VEGF) induced by the Morris water maze task. Mol Cells 33: 295‐300, 2012.
 201.Olenich SA, Audet GN, Roberts KA, Olfert IM. Effects of detraining on the temporal expression of positive and negative angioregulatory proteins in skeletal muscle of mice. J Physiol (Lond) 592: 3325‐3338, 2014.
 202.Olfert IM, Baum O, Hellsten Y, Egginton S. Advances and challenges in skeletal muscle angiogenesis. Am J Physiol Heart & Circ 310: H326‐H336, 2016.
 203.Olfert IM, Howlett RA, Tang K, Dalton ND, Gu Y, Peterson KL, Wagner PD, Breen EC. Muscle‐specific VEGF deficiency greatly reduces exercise endurance in mice. J Physiol (Lond) 587: 1755‐1767, 2009.
 204.Olfert IM, Howlett RA, Wagner PD, Breen EC. Myocyte vascular endothelial growth factor is required for exercise‐induced skeletal muscle angiogenesis. Am J Physiol Regul Integr Comp Physiol 299: R1059‐R1067, 2010.
 205.Oltean S, Neal CR, Mavrou A, Patel P, Ahad T, Alsop C, Lee T, Sison K, Qiu Y, Harper SJ, Bates DO, Salmon AH. VEGF165b overexpression restores normal glomerular water permeability in VEGF164‐overexpressing adult mice. Am J Physiol Renal Physiol 303: F1026‐F1036, 2012.
 206.Oltean S, Qiu Y, Ferguson JK, Stevens M, Neal C, Russell A, Kaura A, Arkill KP, Harris K, Symonds C, Lacey K, Wijeyaratne L, Gammons M, Wylie E, Hulse RP, Alsop C, Cope G, Damodaran G, Betteridge KB, Ramnath R, Satchell SC, Foster RR, Ballmer‐Hofer K, Donaldson LF, Barratt J, Baelde HJ, Harper SJ, Bates DO, Salmon AH. Vascular endothelial growth factor‐A165b is protective and restores endothelial glycocalyx in diabetic nephropathy. J Am Soc Nephrol 26: 1889‐1904, 2015.
 207.Onions K, Betteridge KB, Buckner NR, Gamez M, Bates DO, Welsh GI, Satchell SC, Foster RR. VEGF‐C as an anti‐albuminuric agent. British Microcirculation Society Annual Meeting, Birmingham, UK. Microcirculation, 2017.
 208.Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM, Collen D, Carmeliet P. Deletion of the hypoxia‐response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28: 131‐138, 2001.
 209.Park JE, Chen HH, Winer J, Houck KA, Ferrara N. Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt‐1 but not to Flk‐1/KDR. J Biol Chem 269: 25646‐25654, 1994.
 210.Park SH, Kim KW, Lee YS, Baek JH, Kim MS, Lee YM, Lee MS, Kim YJ. Hypoglycemia‐induced VEGF expression is mediated by intracellular Ca2+ and protein kinase C signaling pathway in HepG2 human hepatoblastoma cells. Int J Mol Med 7: 91‐96, 2001.
 211.Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, Kratz JR, Lin Z, Jain MK, Gimbrone MA, Jr., Garcia‐Cardena G. Integration of flow‐dependent endothelial phenotypes by Kruppel‐like factor 2. J Clin Invest 116: 49‐58, 2006.
 212.Pati S, Orsi SA, Moore AN, Dash PK. Intra‐hippocampal administration of the VEGF receptor blocker PTK787/ZK222584 impairs long‐term memory. Brain Res 1256: 85‐91, 2009.
 213.Perrin RM, Konopatskaya O, Qiu Y, Harper S, Bates DO, Churchill AJ. Diabetic retinopathy is associated with a switch in splicing from anti‐ to pro‐angiogenic isoforms of vascular endothelial growth factor. Diabetologia 48: 2422‐2427, 2005.
 214.Peters S, Heiduschka P, Julien S, Ziemssen F, Fietz H, Bartz‐Schmidt KU, Schraermeyer U. Ultrastructural findings in the primate eye after intravitreal injection of bevacizumab. Am J Ophthalmol 143: 995‐1002, 2007.
 215.Popa GT, Fielding U. The vascular link between the pituitary and the hypothalamus. Lancet 219: 238‐240, 1930.
 216.Prevot V, Croix D, Bouret S, Dutoit S, Tramu G, Stefano GB, Beauvillain JC. Definitive evidence for the existence of morphological plasticity in the external zone of the median eminence during the rat estrous cycle: Implication of neuro‐glio‐endothelial interactions in gonadotropin‐releasing hormone release. Neuroscience 94: 809‐819, 1999.
 217.Qiu Y, Ferguson J, Oltean S, Neal CR, Kaura A, Bevan H, Wood E, Sage LM, Lanati S, Nowak DG, Salmon AH, Bates D, Harper SJ. Overexpression of VEGF165b in podocytes reduces glomerular permeability. J Am Soc Nephrol 21: 1498‐1509, 2010.
 218.Rai S, Nejadhamzeeigilani Z, Gutowski NJ, Whatmore JL. Loss of the endothelial glycocalyx is associated with increased E‐selectin mediated adhesion of lung tumour cells to the brain microvascular endothelium. J Exp Clin Cancer Res 34: 105, 2015.
 219.Real‐Hohn A, Zancan P, Da Silva D, Martins ER, Salgado LT, Mermelstein CS, Gomes AM, Sola‐Penna M. Filamentous actin and its associated binding proteins are the stimulatory site for 6‐phosphofructo‐1‐kinase association within the membrane of human erythrocytes. Biochimie 92: 538‐544, 2010.
 220.Reeson P, Tennant KA, Gerrow K, Wang J, Weiser Novak S, Thompson K, Lockhart KL, Holmes A, Nahirney PC, Brown CE. Delayed inhibition of VEGF signaling after stroke attenuates blood‐brain barrier breakdown and improves functional recovery in a comorbidity‐dependent manner. J Neurosci 35: 5128‐5143, 2015.
 221.Robciuc MR, Kivela R, Williams IM, de Boer JF, van Dijk TH, Elamaa H, Tigistu‐Sahle F, Molotkov D, Leppanen VM, Kakela R, Eklund L, Wasserman DH, Groen AK, Alitalo K. VEGFB/VEGFR1‐induced expansion of adipose vasculature counteracts obesity and related metabolic complications. Cell Metab 23: 712‐724, 2016.
 222.Roberts JR, Perkins GD, Fujisawa T, Pettigrew KA, Gao F, Ahmed A, Thickett DR. Vascular endothelial growth factor promotes physical wound repair and is anti‐apoptotic in primary distal lung epithelial and A549 cells. Crit Care Med 35: 2164‐2170, 2007.
 223.Roberts WG, Palade GE. Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 108: 2369‐2379, 1995.
 224.Ropper AH, Gorson KC, Gooch CL, Weinberg DH, Pieczek A, Ware JH, Kershen J, Rogers A, Simovic D, Schratzberger P, Kirchmair R, Losordo D. Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: A randomized, double‐blinded trial. Ann Neurol 65: 386‐393, 2009.
 225.Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, Betsholtz C, Shima DT. Spatially restricted patterning cues provided by heparin‐binding VEGF‐A control blood vessel branching morphogenesis. Genes Dev 16: 2684‐2698, 2002.
 226.Saaristo A, Veikkola T, Enholm B, Hytonen M, Arola J, Pajusola K, Turunen P, Jeltsch M, Karkkainen MJ, Kerjaschki D, Bueler H, Yla‐Herttuala S, Alitalo K. Adenoviral VEGF‐C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes. Faseb J 16: 1041‐1049, 2002.
 227.Saint‐Geniez M, Kurihara T, Sekiyama E, Maldonado AE, D'Amore PA. An essential role for RPE‐derived soluble VEGF in the maintenance of the choriocapillaris. Proc Natl Acad Sci U S A 106: 18751‐18756, 2009.
 228.Salmon AH, Neal CR, Bates DO, Harper SJ. Vascular endothelial growth factor increases the ultrafiltration coefficient in isolated intact Wistar rat glomeruli. J Physiol 570: 141‐156, 2006.
 229.Salmon AH, Toma I, Sipos A, Muston PR, Harper SJ, Bates DO, Neal CR, Peti‐Peterdi J. Evidence for restriction of fluid and solute movement across the glomerular capillary wall by the subpodocyte space. Am J Physiol Renal Physiol 293: F1777‐F1786, 2007.
 230.Sarelius IH, Glading AJ. Control of vascular permeability by adhesion molecules. Tissue Barriers 3: e985954, 2015.
 231.Satchell SC, Braet F. Glomerular endothelial cell fenestrations: An integral component of the glomerular filtration barrier. Am J Physiol Renal Physiol 296: F947‐F956, 2009.
 232.Savin VJ, Terreros DA. Filtration in single isolated mammalian glomeruli. Kidney Int 20: 188‐197, 1981.
 233.Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T, Shibuya M. Flt‐1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte‐macrophages in humans. Blood 97: 785‐791, 2001.
 234.Schoors S, De Bock K, Cantelmo AR, Georgiadou M, Ghesquiere B, Cauwenberghs S, Kuchnio A, Wong BW, Quaegebeur A, Goveia J, Bifari F, Wang X, Blanco R, Tembuyser B, Cornelissen I, Bouche A, Vinckier S, Diaz‐Moralli S, Gerhardt H, Telang S, Cascante M, Chesney J, Dewerchin M, Carmeliet P. Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab 19: 37‐48, 2014.
 235.Schratzberger P, Walter DH, Rittig K, Bahlmann FH, Pola R, Curry C, Silver M, Krainin JG, Weinberg DH, Ropper AH, Isner JM. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest 107: 1083‐1092, 2001.
 236.Schumacher VA, Jeruschke S, Eitner F, Becker JU, Pitschke G, Ince Y, Miner JH, Leuschner I, Engers R, Everding AS, Bulla M, Royer‐Pokora B. Impaired glomerular maturation and lack of VEGF165b in Denys‐Drash syndrome. J Am Soc Nephrol 18: 719‐729, 2007.
 237.Schwarte‐Waldhoff I, Volpert OV, Bouck NP, Sipos B, Hahn SA, Klein‐Scory S, Luttges J, Kloppel G, Graeven U, Eilert‐Micus C, Hintelmann A, Schmiegel W. Smad4/DPC4‐mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci U S A 97: 9624‐9629, 2000.
 238.Schwenk RW, Luiken JJ, Bonen A, Glatz JF. Regulation of sarcolemmal glucose and fatty acid transporters in cardiac disease. Cardiovasc Res 79: 249‐258, 2008.
 239.Selvaraj D, Gangadharan V, Michalski CW, Kurejova M, Stösser S, Srivastava K, Schweizerhof M, Waltenberger J, Ferrara N, Heppenstall P, Shibuya M, Augustin HG, Kuner R. A functional role for VEGFR1 expressed in peripheral sensory neurons in cancer pain. Cancer Cell 27: 780‐796, 2015.
 240.Semenza GL. HIF‐1: Using two hands to flip the angiogenic switch. Cancer Metastasis Rev 19: 59‐65, 2000.
 241.Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC. Failure of blood‐island formation and vasculogenesis in Flk‐1‐deficient mice. Nature 376: 62‐66, 1995.
 242.Shojaei F, Wu X, Malik AK, Zhong C, Baldwin ME, Schanz S, Fuh G, Gerber HP, Ferrara N. Tumor refractoriness to anti‐VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat Biotechnol 25: 911‐920, 2007.
 243.Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, Blanchard D, Bais C, Peale FV, van Bruggen N, Ho C, Ross J, Tan M, Carano RA, Meng YG, Ferrara N. Bv8 regulates myeloid‐cell‐dependent tumour angiogenesis. Nature 450: 825‐831, 2007.
 244.Shyy YJ, Hsieh HJ, Usami S, Chien S. Fluid shear stress induces a biphasic response of human monocyte chemotactic protein 1 gene expression in vascular endothelium. Proc Natl Acad Sci U S A 91: 4678‐4682, 1994.
 245.Singh A, Satchell SC, Neal CR, McKenzie EA, Tooke JE, Mathieson PW. Glomerular endothelial glycocalyx constitutes a barrier to protein permeability. J Am Soc Nephrol 18: 2885‐2893, 2007.
 246.Soker S, Fidder H, Neufeld G, Klagsbrun M. Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumor cells that bind VEGF165 via its exon 7‐encoded domain. J Biol Chem 271: 5761‐5767, 1996.
 247.Sondell M, Kanje M. Postnatal expression of VEGF and its receptor flk‐1 in peripheral ganglia. Neuroreport 12: 105‐108, 2001.
 248.Sondell M, Lundborg G, Kanje M. Vascular endothelial growth factor has neurotrophic activity and stimulates axonal outgrowth, enhancing cell survival and Schwann cell proliferation in the peripheral nervous system. J Neurosci 19: 5731‐5740, 1999.
 249.Sondell M SF, Kanje M. Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk‐1 receptor. Eur J Neurosci 12: 4243‐4254, 2000.
 250.Spitzer MS, Wallenfels‐Thilo B, Sierra A, Yoeruek E, Peters S, Henke‐Fahle S, Bartz‐Schmidt KU, Szurman P. Antiproliferative and cytotoxic properties of bevacizumab on different ocular cells. Br J Ophthalmol 90: 1316‐1321, 2006.
 251.Steinberg RH, Wood I, Hogan MJ. Pigment epithelial ensheathment and phagocytosis of extrafoveal cones in human retina. Philos Trans R Soc Lon B Biol Sci 277: 459‐474, 1977.
 252.Stone OA, Carter JG, Lin PC, Paleolog E, Machado MJ, Bates DO. Differential regulation of blood flow induced neovascularisation and mural cell recruitment by VEGF and angiopoietin signalling. J Physiol 595(5): 1575‐1591, 2017.
 253.Storkebaum E, Lambrechts D, Dewerchin M, Moreno‐Murciano MP, Appelmans S, Oh H, Van Damme P, Rutten B, Man WY, De Mol M, Wyns S, Manka D, Vermeulen K, Van Den Bosch L, Mertens N, Schmitz C, Robberecht W, Conway EM, Collen D, Moons L, Carmeliet P. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature neuroscience 8: 85‐92, 2005.
 254.Sugimoto H, Hamano Y, Charytan D, Cosgrove D, Kieran M, Sudhakar A, Kalluri R. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti‐VEGF antibodies and soluble VEGF receptor 1 (sFlt‐1) induces proteinuria. J Biol Chem 278: 12605‐12608, 2003.
 255.Sun K, Wernstedt Asterholm I, Kusminski CM, Bueno AC, Wang ZV, Pollard JW, Brekken RA, Scherer PE. Dichotomous effects of VEGF‐A on adipose tissue dysfunction. Proc Natl Acad Sci U S A 109: 5874‐5879, 2012.
 256.Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA. VEGF‐induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111: 1843‐1851, 2003.
 257.Takyar S, Vasavada H, Zhang JG, Ahangari F, Niu N, Liu Q, Lee CG, Cohn L, Elias JA. VEGF controls lung Th2 inflammation via the miR‐1‐Mpl (myeloproliferative leukemia virus oncogene)‐P‐selectin axis. J Exp Med 210: 1993‐2010, 2013.
 258.Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovasc Res 65: 550‐563, 2005.
 259.Tang K, Rossiter HB, Wagner PD, Breen EC. Lung‐targeted VEGF inactivation leads to an emphysema phenotype in mice. J Appl Physiol (1985) 97: 1559‐1566; discussion 1549, 2004.
 260.Taylor S, Trudeau D, Arnold B, Wang J, Gerrow K, Summerfeldt K, Holmes A, Zamani A, Brocardo P, Brown C. VEGF can protect against blood brain barrier dysfunction, dendritic spine loss and spatial memory impairment in an experimental model of diabetes. Neurobiol Dis 78: 11, 2015.
 261.Tesfaye S, Malik R, Ward JD. Vascular factors in diabetic neuropathy. Diabetologia 37: 847‐854, 1994.
 262.Textor B, Sator‐Schmitt M, Richter KH, Angel P, Schorpp‐Kistner M. c‐Jun and JunB are essential for hypoglycemia‐mediated VEGF induction. Ann N Y Acad Sci 1091: 310‐318, 2006.
 263.Thaler S, Fiedorowicz M, Choragiewicz TJ, Bolz S, Tura A, Henke‐Fahle S, Yoeruek E, Zrenner E, Bartz‐Schmidt KU, Ziemssen F, Schuettauf F. Toxicity testing of the VEGF inhibitors bevacizumab, ranibizumab and pegaptanib in rats both with and without prior retinal ganglion cell damage. Acta Ophthalmol 88: e170‐e176, 2010.
 264.Thi MM, Iacobas DA, Iacobas S, Spray DC. Fluid shear stress upregulates vascular endothelial growth factor gene expression in osteoblasts. Ann N Y Acad Sci 1117: 73‐81, 2007.
 265.Tsantoulas C, Zhu L, Shaifta Y, Grist J, Ward JP, Raouf R, Michael GJ, McMahon SB. Sensory neuron downregulation of the Kv9.1 potassium channel subunit mediates neuropathic pain following nerve injury. J Neurosci 32: 17502‐17513, 2012.
 266.Tsao PN, Su YN, Li H, Huang PH, Chien CT, Lai YL, Lee CN, Chen CA, Cheng WF, Wei SC, Yu CJ, Hsieh FJ, Hsu SM. Overexpression of placenta growth factor contributes to the pathogenesis of pulmonary emphysema. Am J Respir Crit Care Med 169: 505‐511, 2004.
 267.Tschulakow A, Christner S, Julien S, Ludinsky M, van der Giet M, Schraermeyer U. Effects of a single intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys. PLoS One 9: e113701, 2014.
 268.Tuder RM, Kasahara Y, Voelkel NF. Inhibition of vascular endothelial growth factor receptors causes emphysema in rats. Chest 117: 281S, 2000.
 269.Uchida C, Nwadozi E, Hasanee A, Olenich S, Olfert IM, Haas TL. Muscle‐derived vascular endothelial growth factor regulates microvascular remodelling in response to increased shear stress in mice. Acta Physiol 214: 349‐360, 2015.
 270.van Neerven S, Joosten EA, Brook GA, Lambert CA, Mey J, Weis J, Marcus MA, Steinbusch HW, van Kleef M, Patijn J, Deumens R. Repetitive intrathecal VEGF(165) treatment has limited therapeutic effects after spinal cord injury in the rat. J Neurotrauma 27: 1781‐1791, 2010.
 271.Van Schaftingen E, Lederer B, Bartrons R, Hers HG. A kinetic study of pyrophosphate: fructose‐6‐phosphate phosphotransferase from potato tubers. Application to a microassay of fructose 2,6‐bisphosphate. Eur J Biochem 129: 191‐195, 1982.
 272.Van Vught PW, Sutedja NA, Veldink JH, Koeleman BP, Groeneveld GJ, Wijmenga C, Uitdehaag BM, de Jong JM, Baas F, Wokke JH, Van den Berg LH. Lack of association between VEGF polymorphisms and ALS in a Dutch population. Neurology 65: 1643‐1645, 2005.
 273.Varet J, Douglas SK, Gilmartin L, Medford AR, Bates DO, Harper SJ, Millar AB. VEGF in the lung: A role for novel isoforms. Am J Physiol Lung Cell Mol Physiol 298: L768‐L774, 2010.
 274.Ved N, Hulse RP, Bestall SM, Donaldson LF, Bainbridge JW, Bates DO. Vascular endothelial growth factor‐A165b ameliorates outer‐retinal barrier and vascular dysfunction in the diabetic retina. Clin Sci (Lond) 131(12): 1225‐1243, 2017.
 275.Vencappa S, Donaldson LF, Hulse RP. Cisplatin induced sensory neuropathy is prevented by vascular endothelial growth factor‐A. Am J Transl Res 7: 1032‐1044, 2015.
 276.Venneri MA, De Palma M, Ponzoni M, Pucci F, Scielzo C, Zonari E, Mazzieri R, Doglioni C, Naldini L. Identification of proangiogenic TIE2‐expressing monocytes (TEMs) in human peripheral blood and cancer. Blood 109: 5276‐5285, 2007.
 277.Verheyen A, Peeraer E, Nuydens R, Dhondt J, Poesen K, Pintelon I, Daniels A, Timmermans JP, Meert T, Carmeliet P, Lambrechts D. Systemic anti‐vascular endothelial growth factor therapies induce a painful sensory neuropathy. Brain 135: 2629‐2641, 2012.
 278.Veron D, Reidy K, Marlier A, Bertuccio C, Villegas G, Jimenez J, Kashgarian M, Tufro A. Induction of podocyte VEGF164 overexpression at different stages of development causes congenital nephrosis or steroid‐resistant nephrotic syndrome. Am J Pathol 177: 2225‐2233, 2010.
 279.Veron D, Reidy KJ, Bertuccio C, Teichman J, Villegas G, Jimenez J, Shen W, Kopp JB, Thomas DB, Tufro A. Overexpression of VEGF‐A in podocytes of adult mice causes glomerular disease. Kidney Int 77: 989‐999, 2010.
 280.Vestweber D. How leukocytes cross the vascular endothelium. Nat Rev Immunol 15: 692‐704, 2015.
 281.Vogel K, Kuhn J, Kleesiek K, Gotting C. A novel ultra‐sensitive method for the quantification of glycosaminoglycan disaccharides using an automated DNA sequencer. Electrophoresis 27: 1363‐1367, 2006.
 282.Wang Y, Kilic E, Kilic U, Weber B, Bassetti CL, Marti HH, Hermann DM. VEGF overexpression induces post‐ischaemic neuroprotection, but facilitates haemodynamic steal phenomena. Brain 128: 52‐63, 2005.
 283.Waters RE, Rotevatn S, Li P, Annex BH, Yan Z. Voluntary running induces fiber type‐specific angiogenesis in mouse skeletal muscle. Am J Physiol Cell Physiol 287: C1342‐C1348, 2004.
 284.Weil EJ, Lemley KV, Mason CC, Yee B, Jones LI, Blouch K, Lovato T, Richardson M, Myers BD, Nelson RG. Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int 82: 1010‐1017, 2012.
 285.Weinberger D, Fink‐Cohen S, Gaton DD, Priel E, Yassur Y. Non‐retinovascular leakage in diabetic maculopathy. Br J Ophthalmol 79: 728‐731, 1995.
 286.Williams JL, Cartland D, Hussain A, Egginton S. A differential role for nitric oxide in two forms of physiological angiogenesis in mouse. J Physiol 570: 445‐454, 2006.
 287.Williams JL, Cartland D, Rudge JS, Egginton S. VEGF trap abolishes shear stress‐ and overload‐dependent angiogenesis in skeletal muscle. Microcirculation 13: 499‐509, 2006.
 288.Winkler BS, Boulton ME, Gottsch JD, Sternberg P. Oxidative damage and age‐related macular degeneration. Mol Vis 5: 32, 1999.
 289.Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard‐Jones RO, Cui TG, Sugiono M, Waine E, Perrin R, Foster R, Digby‐Bell J, Shields JD, Whittles CE, Mushens RE, Gillatt DA, Ziche M, Harper SJ, Bates DO. VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res 64: 7822‐7835, 2004.
 290.Wu WK, Llewellyn OP, Bates DO, Nicholson LB, Dick AD. IL‐10 regulation of macrophage VEGF production is dependent on macrophage polarisation and hypoxia. Immunobiology 215: 796‐803, 2010.
 291.Xu HZ, Song Z, Fu S, Zhu M, Le YZ. RPE barrier breakdown in diabetic retinopathy: Seeing is believing. J Ocul Biol Dis Infor 4: 83‐92, 2011.
 292.Yamamura T, Hirunagi K, Ebihara S, Yoshimura T. Seasonal morphological changes in the neuro‐glial interaction between gonadotropin‐releasing hormone nerve terminals and glial endfeet in Japanese quail. Endocrinology 145: 4264‐4267, 2004.
 293.Yao JS, Shen F, Young WL, Yang GY. Comparison of doxycycline and minocycline in the inhibition of VEGF‐induced smooth muscle cell migration. Neurochem Int 50: 524‐530, 2007.
 294.Yeomans A, Thompson N, Castle‐Miller J, Bates DO, Tortonese DJ. Mechanisms underlying pituitary microvasculature remodelling in Thoroughbred horses during the annual reproductive cycle. World Congress of Reproductive Biology, Edinburgh, UK, 2014.
 295.Zachwieja NJ, O'Connell GC, Stricker JC, Allen J, Vona‐Davis L, Bryner R, Mandler W, Olfert IM. Loss of adipocyte VEGF impairs endurance exercise capacity in mice. Med Sci Sports Exerc 47: 2329‐2339, 2015.
 296.Zhang F, Tang Z, Hou X, Lennartsson J, Li Y, Koch AW, Scotney P, Lee C, Arjunan P, Dong L, Kumar A, Rissanen TT, Wang B, Nagai N, Fons P, Fariss R, Zhang Y, Wawrousek E, Tansey G, Raber J, Fong GH, Ding H, Greenberg DA, Becker KG, Herbert JM, Nash A, Yla‐Herttuala S, Cao Y, Watts RJ, Li X. VEGF‐B is dispensable for blood vessel growth but critical for their survival, and VEGF‐B targeting inhibits pathological angiogenesis. Proc Natl Acad Sci U S A 106: 6152‐6157, 2009.
 297.Zhang L, Yu D, Hu M, Xiong S, Lang A, Ellis LM, Pollock RE. Wild‐type p53 suppresses angiogenesis in human leiomyosarcoma and synovial sarcoma by transcriptional suppression of vascular endothelial growth factor expression. Cancer Res 60: 3655‐3661, 2000.
 298.Zheng C, Nennesmo I, Fadeel B, Henter JI. Vascular endothelial growth factor prolongs survival in a transgenic mouse model of ALS. Ann Neurol 56: 564‐567, 2004.
 299.Zhou Y, Bellingard V, Feng KT, McMaster M, Fisher SJ. Human cytotrophoblasts promote endothelial survival and vascular remodeling through secretion of Ang2, PlGF, and VEGF‐C. Dev Biol 263: 114‐125, 2003.

Contact Editor

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

* Required Field

How to Cite

David O. Bates, Nicholas Beazley‐Long, Andrew V. Benest, Xi Ye, Nikita Ved, Richard P. Hulse, Shaney Barratt, Maria J. Machado, Lucy F. Donaldson, Steven J. Harper, Maria Peiris‐Pages, Domingo J. Tortonese, Sebastian Oltean, Rebecca R. Foster. Physiological Role of Vascular Endothelial Growth Factors as Homeostatic Regulators. Compr Physiol 2018, 8: 955-979. doi: 10.1002/cphy.c170015