A Review on Angiogenesis and Its Assays

Document Type: Review Article


Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran.


Angiogenesis or formation of new blood vessels from preexisting vasculature is a key process in some physiological conditions such as wound healing, growth, and action of female reproductive organs. Moreover, disturbance of the mechanisms of physiological angiogenesis has a role in pathogenesis of some diseases in the form of overproliferation of blood vessels such as cancers, psoriasis, arthritis, retinopathies, obesity, asthma, and atherosclerosis or impaired angiogenesis participates in diseases such as heart and brain ischemia, neurodegeneration, hypertension, osteoporosis, respiratory distress, preeclampsia, endometriosis, postpartum cardiomyopathy, and ovarian hyperstimulation syndrome. Research and study in angiogenesis provide a potential to cure a variety of diseases such as cancers or cardiovascular diseases. Thus, in recent years, several methods for evaluation of angiogenesis have been introduced and selecting the most appropriate cure is very important. In this article, first, we briefly reviewed appropriate assays to evaluate therapeutic angiogenesis (clinical manipulation of angiogenesis) and its importance during some clinical diseases and then introduced in vitro, in vivo, and ex vivo assays of angiogenesis besides their benefits and disadvantages. Next, some quantitative techniques for assessing angiogenesis have been discussed.


1. Drake CJ. Embryonic and adult vasculogenesis. Birth Defects Res C Embryo Today 2003;69:73-82.

2. Zygmunt M, Herr F, Munstedt K, Lang U, Liang OD. Angiogenesis and vasculogenesis in pregnancy. Eur J Obstet Gynecol Reprod Biol 2003; 110:S10-S18.

3. Carmeliet P. Angiogenesis in health and disease. Nat Med 2003;9:653-660.

4. Charnock-Jones DS, Kaufmann P, Mayhew TM. Aspects of human fetoplacental vasculogenesis and angiogenesis. I. Molecular regulation. Placenta 2004; 25:103-113.

5. Fraser HM, Duncan WC. Vascular morphogenesis in the primate ovary. Angiogenesis 2005;8:101-1016.

6. Fraser HM, Lunn SF. Angiogenesis and its control in the female reproductive system. Br Med Bull 2000; 56:787-797.

7. Girling JE, Rogers PA. Recent advances in endometrial angiogenesis research. Angiogenesis 2005; 8:89-99.

8. Brown MD, Hudlicka O. Modulation of physiological angiogenesis in skeletal muscle by mechanical forces: involvement of VEGF and metalloproteinases. Angiogenesis 2003; 6:1-14.

9. Williams JL, Weichert A, Zakrzewicz A, Da Silva-Azevedo L, Pries AR, Baum O, et al. Differential gene and protein expression in abluminal sprouting and intraluminal splitting forms of angiogenesis. Clin Sci (Lond) 2006; 110:587-595.

10. Gould J, Aramburo C, Capdevielle M, Scanes CG. Angiogenic activity of anterior pituitary tissue and growth hormone on the chick embryo chorio-allantoic membrane: a novel action of GH. Life Sci 1995; 56:587-594.

11. Gerhardt H, Betsholtz C. Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 2003; 314:15-23.

12. Hershey JC, Baskin EP, Glass JD, Hartman HA, Gilberto DB, Rogers IT, et al. Revascularization in the rabbit hindlimb: dissociation between capillary sprouting and arteriogenesis. Cardiovasc Res 2001; 49:618-625.

13. Van RN, Piek JJ, Buschmann I, Hoefer I, Voskuil M, Schaper W. Stimulation of arteriogenesis; a new concept for the treatment of arterial occlusive disease. Cardiovasc Res 2001; 49:543-553.

14. Karamysheva AF. Mechanisms of angiogenesis. Biochemistry (Mosc ) 2008; 73:751-762.

15. Sainson RC, Aoto J, Nakatsu MN, Holderfield M, Conn E, Koller E, et al. Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J 2005; 19:1027-1029.

16. Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, Dotto GP, et al. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 2003; 23:14-25.

17. Radtke F, Schweisguth F, Pear W. The Notch 'gospel'. EMBO Rep 2005; 6:1120-1125.

18. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 2003; 161:1163-1177.

19. Jain RK. Molecular regulation of vessel maturation. Nat Med 2003; 9:685-693.

20. Cleaver O, Melton DA. Endothelial signaling during development. Nat Med 2003; 9:661-668.

21. Baluk P, Hashizume H, McDonald DM. Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev 2005; 15:102-111.

22. Betsholtz C. Insight into the physiological functions of PDGF through genetic studies in mice. Cytokine Growth Factor Rev 2004; 15:215-228.

23. Fredriksson L, Li H, Eriksson U. The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev 2004; 15:197-204.

24. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 2003; 9:677-684.

25. Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000; 6:389-395.

26. Salehi E, Amjadi F, Khazaei M. Angiogenesis in health and disease: Role of vascular endothelial growth factor (VEGF) J Isfahan Med School 2011; 29: 1-15.

27. Distler JH, Hirth A, Kurowska-Stolarska M, Gay RE, Gay S, Distler O. Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med 2003; 47:149-161.

28. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 2000; 60:203-212.

29. Shushanov S, Bronstein M, Adelaide J, Jussila L, Tchipysheva T, Jacquemier J, et al. VEGFc and VEGFR3 expression in human thyroid pathologies. Int J Cancer 2000; 86:47-52.

30. Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA 2002; 99:11205-11210.

31. Etoh T, Inoue H, Tanaka S, Barnard GF, Kitano S, Mori M. Angiopoietin-2 is related to tumor angiogenesis in gastric carcinoma: possible in vivo regulation via induction of proteases. Cancer Res 2001; 61:2145-2153.

32. Kedar D, Baker CH, Killion JJ, Dinney CP, Fidler IJ. Blockade of the epidermal growth factor receptor signaling inhibits angiogenesis leading to regression of human renal cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 2002; 8:3592-3600.

33. Baselga J. Why the epidermal growth factor receptor? The rationale for cancer therapy. Oncologist 2002; 7:2-8.

34. Ravindranath N, Wion D, Brachet P, Djakiew D. Epidermal growth factor modulates the expression of vascular endothelial growth factor in the human prostate. J Androl 2001; 22:432-443.

35. Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 2000; 7:165-197.

36. Miller DL, Ortega S, Bashayan O, Basch R, Basilico C. Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol 2000; 20:2260-2268.

37. Mattila MM, Ruohola JK, Valve EM, Tasanen MJ, Seppanen JA, Harkonen PL. FGF-8b increases angiogenic capacity and tumor growth of androgen-regulated S115 breast cancer cells. Oncogene 2001; 20:2791-2804.

38. Pozzi A, Moberg PE, Miles LA, Wagner S, Soloway P, Gardner HA. Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. Proc Natl Acad Sci USA 2000; 97:2202-2207.

39. Felbor U, Dreier L, Bryant RA, Ploegh HL, Olsen BR, Mothes W. Secreted cathepsin L generates endostatin from collagen XVIII. EMBO J 2000; 19:1187-1194.

40. MacDonald NJ, Shivers WY, Narum DL, Plum SM, Wingard JN, Fuhrmann SR, et al. Endostatin binds tropomyosin. A potential modulator of the antitumor activity of endostatin. J Biol Chem 2001; 276:25190-25196.

41. Bloch W, Huggel K, Sasaki T, Grose R, Bugnon P, Addicks K, et al. The angiogenesis inhibitor endostatin impairs blood vessel maturation during wound healing. FASEB J 2000; 14:2373-2376.

42. Lawler J. The functions of thrombospondin-1 and-2. Curr Opin Cell Biol 2000; 12:634-640.

43. Jimenez B, Volpert OV, Crawford SE, Febbraio M, Silverstein RL, Bouck N. Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med 2000; 6:41-48.

44. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9:669-676.

45. Zarei M, Khazaei M, Sharifi MR, Pourshanazari AA. Coronary angiogenesis during experimental hypertension: it is reversible? JRMS 2011; 16:269-275.

46. Amjadi F, Javanmard SH, Zarkesh-Esfahani H, Khazaei M, Narimani M. Leptin promotes melanoma tumor growth in mice related to increasing circulating endothelial progenitor cells numbers and plasma NO production. J Exp Clin Cancer Res 2011; 30:21.

47. Khazaei M, Fallahzadeh AR, Sharifi MR, Afsharmoghaddam N, Javanmard SH, Salehi E. Effects of diabetes on myocardial capillary density and serum angiogenesis biomarkers in male rats. Clinics (Sao Paulo) 2011; 66:1419-1424.

48. Carmeliet P. Angiogenesis in life, disease and medicine. Nature 2005; 438:932-936.

49. Paul SA, Simons JW, Mabjeesh NJ. HIF at the crossroads between ischemia and carcinogenesis. J Cell Physiol 2004; 200:20-30.

50. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation 2002; 105:939-943.

51. Libby P. Inflammation in atherosclerosis. Natur 2002; 420:868-874.

52. Yla-Herttuala S, Rissanen TT, Vajanto I, Hartikainen J. Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol 2007; 49:1015-1026.

53. Laham RJ, Sellke FW, Edelman ER, Pearlman JD, Ware JA, Brown DL, et al. Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary by pass surgery: results of phase 1 randomized double blind, placebo-controlled trial.Circulation 1999;100:1865-71.

54. Figg WD FJ. Angiogenesis:an integrative approach from science to medicine. New York:Springer; 2008.

55. Dome B, Hendrix MJ, Paku S, Tovari J, Timar J. Alternative vascularization mechanisms in cancer: Pathology and therapeutic implications. Am J Pathol 2007; 170:1-15.

56. Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 2001; 7:1194-1201.

57. Gordon MS, Mendelson DS, Kato G. Tumor angiogenesis and novel antiangiogenic strategies. Int J Cancer 2010; 126:1777-1787.

58. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335-2342.

59. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357:2666-2676.

60. Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2008; 26:1810-1816.

61. Hood JD, Bednarski M, Frausto R, Guccione S, Reisfeld RA, Xiang R, et al. Tumor regression by targeted gene delivery to the neovasculature. Science 2002; 296:2404-2407.

62. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005; 365:785-799.

63. Charnock-Jones DS, Burton GJ. Placental vascular morphogenesis. Baillieres Best Pract Res Clin Obstet Gynaecol 2000; 14:953-968.

64. Stallmach T, Duc C, van PE, Mumenthaler C, Ott C, Kolb SA, et al. Feto-maternal interface of human placenta inhibits angiogenesis in the chick chorioallantoic membrane (CAM) assay. Angiogenesis 2001; 4:79-84.

65. Bdolah Y, Sukhatme VP, Karumanchi SA. Angiogenic imbalance in the pathophysiology of preeclampsia: newer insights. Semin Nephrol 2004; 24:548-556.

66. Irani RA, Xia Y. The functional role of the renin-angiotensin system in pregnancy and preeclampsia. Placenta 2008; 29:763-771.

67. Hornig C, Barleon B, Ahmad S, Vuorela P, Ahmed A, Weich HA. Release and complex formation of soluble VEGFR-1 from endothelial cells and biological fluids. Lab Invest 2000; 80:443-454.

68. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. Retinopathy in diabetes. Diabetes Care 2004; 27:S84-S87.

69. Knudsen ST, Bek T, Poulsen PL, Hove MN, Rehling M, Mogensen CE. Macular edema reflects generalized vascular hyperpermeability in type 2 diabetic patients with retinopathy. Diabetes Care 2002; 25:2328-2334.

70. Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog Retin Eye Res 2008; 27:622-647.

71. Soucek T, Cumming R, Dargusch R, Maher P, Schubert D. The regulation of glucose metabolism by HIF-1 mediates a neuroprotective response to amyloid beta peptide. Neuron 2003; 39:43-56.

72. Frank RN. Diabetic retinopathy. N Engl J Med 2004; 350:48-58.

73. Crawford TN, Alfaro DV, III, Kerrison JB, Jablon EP. Diabetic retinopathy and angiogenesis. Curr Diabetes Rev 2009; 5:8-13.

74. Funatsu H, Yamashita H, Noma H, Shimizu E, Yamashita T, Hori S. Stimulation and inhibition of angiogenesis in diabetic retinopathy. Jpn J Ophthalmol 2001; 45:577-584.

75. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003 15; 423:356-361.

76. Barrett EM, Scott DG, Wiles NJ, Symmons DP. The impact of rheumatoid arthritis on employment status in the early years of disease: a UK community-based study. Rheumatology (Oxford) 2000; 39:1403-1409.

77. Szekanecz Z, Gaspar L, Koch AE. Angiogenesis in rheumatoid arthritis. Front Biosci 2005; 10:1739-1753.

78. Szekanecz Z, Koch AE. Targeting Angiogenesis in Rheumatoid Arthritis. Curr Rheumatol Rev 2008; 4:298-303.

79. Paleolog EM. The vasculature in rheumatoid arthritis: cause or consequence? Int J Exp Pathol 2009; 90:249-261.

80. Thairu N, Kiriakidis S, Dawson P, Paleolog E. Angiogenesis as a therapeutic target in arthritis in 2011: learning the lessons of the colorectal cancer experience. Angiogenesis 2011; 14: 223-234.

81. Lee YA, Kim JY, Hong SJ, Lee SH, Yoo MC, Kim KS, et al. Synovial proliferation differentially affects hypoxia in the joint cavities of rheumatoid arthritis and osteoarthritis patients. Clin Rheumatol 2007; 26:2023-2029.

82. Giatromanolaki A, Sivridis E, Maltezos E, Athanassou N, Papazoglou D, Gatter KC, et al. Upregulated hypoxia inducible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 2003; 5:R193-R201.

83. Baghaban Eslaminejad, Bagheri, Zomorodian, E. Matrigel enhances in vitro Bone differentiation of human marrow-derived mesenchymal stem cells. Iran J Basic Med Sic 2010; 13:187-194.

84. Malinda KM. In vivo matrigel migration and angiogenesis assay. Methods Mol Biol 2009; 467:287-294.

85. Hasan J, Shnyder SD, Bibby M, Double JA, Bicknel R, Jayson GC. Quantitative angiogenesis assays in vivo-a review. Angiogenesis 2004; 7:1-16.

86. Lee KH, Choi HR, Kim CH. Anti-angiogenic effect of the seed extract of Benincasa hispida Cogniaux. J Ethnopharmacol 2005; 97:509-513.

87. Norrby K. In vivo models of angiogenesis. J Cell Mol Med 2006; 10:588-612.

88. Staton CA, Stribbling SM, Tazzyman S, Hughes R, Brown NJ, Lewis CE. Current methods for assaying angiogenesis in vitro and in vivo. Int J Exp Pathol 2004; 85:233-248.

89.Fallahzadeh AR, Khazaei M, Sharifi MR. Restoration of angiogenesis by enalapril in diabetic hindlimb ischemc rats. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2011; 155:137-142.

90. http://www.osnsupersite.com/images/osn

91. Auerbach R, Lewis R, Shinners B, Kubai L, Akhtar N. Angiogenesis assays: a critical overview. Clin Chem 2003; 49:32-40.

92. Ribatti D, Nico B, Vacca A, Roncali L, Burri PH, Djonov V. Chorioallantoic membrane capillary bed: a useful target for studying angiogenesis and anti-angiogenesis in vivo. Anat Rec 2001; 264:317-324.

93. http://www.currentprotocols.com/protocol/

94. Van WV, Toes RE, Seghers L, Deckers MM, de Vries MR, Eilers PH, et al. Natural killer cells and CD4+ T-cells modulate collateral artery development. Arterioscler Thromb Vasc Biol 2007; 27:2310-2318.

95. Couffinhal T, Dufourcq P, Barandon L, Leroux L, Duplaa C. Mouse models to study angiogenesis in the context of cardiovascular diseases. Front Biosci 2009; 14:3310-3325.

96. Emanueli C, Minasi A, Zacheo A, Chao J, Chao L, Salis MB, et al. Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Circulation 2001; 103:125-132.

97. http://www2.massgeneral.org/plasticsurgerylab/images/limb

98. Staton CA, Reed MW, Brown NJ. A critical analysis of current in vitro and in vivo angiogenesis assays. Int J Exp Pathol 2009; 90:195-221.

99. Gomez D, Reich NC. Stimulation of primary human endothelial cell proliferation by IFN. J Immunol 2003; 170:5373-5381.

100. Albini A, Benelli R, Noonan DM, Brigati C. The "chemoinvasion assay": a tool to study tumor and endothelial cell invasion of basement membranes. Int J Dev Biol 2004; 48:563-571.

101. Smith JT, Tomfohr JK, Wells MC, Beebe TP, Jr., Kepler TB, Reichert WM. Measurement of cell migration on surface-bound fibronectin gradients. Langmuir 2004; 20:8279-8286.

102. Segura I, Serrano A, De Buitrago GG, Gonzalez MA, Abad JL, Claveria C, et al. Inhibition of programmed cell death impairs in vitro vascular-like structure formation and reduces in vivo angiogenesis. FASEB J 2002; 16:833-841.

103. Gagnon E, Cattaruzzi P, Griffith M, Muzakare L, LeFlao K, Faure R, et al. Human vascular endothelial cells with extended life spans: in vitro cell response, protein expression, and angiogenesis. Angiogenesis 2002; 5:21-33.

104. Donovan D, Brown NJ, Bishop ET, Lewis CE. Comparison of three in vitro human 'angiogenesis' assays with capillaries formed in vivo. Angiogenesis 2001; 4:113-121.

105. Friis T, Kjaer SB, Engel AM, Rygaard J, Houen G. A quantitative ELISA-based co-culture angiogenesis and cell proliferation assay. APMIS 2003; 111:658-668.

106. Huerta S, Goulet EJ, Huerta-Yepez S, Livingston EH. Screening and detection of apoptosis. J Surg Res 2007; 139:143-156.

107. Eccles SA, Box C, Court W. Cell migration/invasion assays and their application in cancer drug discovery. Biotechnol Annu Rev 2005; 11:391-421.

108. Nakano M, Satoh K, Fukumoto Y, Ito Y, Kagaya Y, Ishii N, et al. Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice. Circ Res 2007; 100:662-669.

109. Jung SP, Siegrist B, Wade MR, Anthony CT, Woltering EA. Inhibition of human angiogenesis with heparin and hydrocortisone. Angiogenesis 2001; 4:175-186.

110. Muthukkaruppan VR, Shinneers BL, Lewis R, Park SJ, Baechler BJ, Auerbach R. The chick embryo aortic arch assay: a new, rapid, quantifiable in vitro method for testing the efficacy of angiogenic and anti-angiogenic factors in a three-dimentional, serum-free organ culture system. Proc Am Assoc Cancer Res 2000; 41:65.

111. Oh SH, Woo JK, Jin Q, Kang HJ, Jeong JW, Kim KW, et al. Identification of novel antiangiogenic anticancer activities of deguelin targeting hypoxia-inducible factor-1 alpha. Int J Cancer 2008; 122:5-14.

112. McDonald DM, Choyke PL. Imaging of angiogenesis: from microscope to clinic. Nat Med 2003; 9:713-725.

113. Neeman M, Dafni H. Structural, functional, and molecular MR imaging of the microvasculature. Annu Rev Biomed Eng 2003; 5:29-56.

114. Hasan J, Byers R, Jayson GC. Intra-tumoural microvessel density in human solid tumours. Br J Cancer 2002; 86:1566-1577.

115. Capoccia BJ, Shepherd RM, Link DC. G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism. Blood 2006; 108:2438-2445.

116. Li W, Shen W, Gill R, Corbly A, Jones B, Belagaje R, et al. High-resolution quantitative computed tomography demonstrating selective enhancement of medium-size collaterals by placental growth factor-1 in the mouse ischemic hindlimb. Circulation 2006; 113:2445-2453.

117. Foubert P, Silvestre JS, Souttou B, Barateau V, Martin C, Ebrahimian TG, et al. PSGL-1-mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells. J Clin Invest 2007; 117:1527-1537.

118. Di SS, Yang Z, Wyler von BM, Voelzmann J, Diehm N, Baumgartner I, et al. Novel cell-free strategy for therapeutic angiogenesis: in vitro generated conditioned medium can replace progenitor cell transplantation. PLoS One 2009; 4:e5643.

119. Jacobi J, Tam BY, Wu G, Hoffman J, Cooke JP, Kuo CJ. Adenoviral gene transfer with soluble vascular endothelial growth factor receptors impairs angiogenesis and perfusion in a murine model of hindlimb ischemia. Circulation 2004; 110:2424-2429.

120. Cheranov SY, Karpurapu M, Wang D, Zhang B, Venema RC, Rao GN. An essential role for SRC-activated STAT-3 in 14,15-EET-induced VEGF expression and angiogenesis. Blood 2008; 111:5581-5591.

121. Lu Y, Xiong Y, Huo Y, Han J, Yang X, Zhang R, et al. Grb-2-associated binder 1 (Gab1) regulates postnatal ischemic and VEGF-induced angiogenesis through the protein kinase A-endothelial NOS pathway. Proc Natl Acad Sci USA 2011; 108:2957-2962.