A key central stage of wound healing requires neovascularization of the wound base granulation tissue. In the adult, neovascularization is now known to occur by both angiogenesis and vasculogenesis. Understanding the biology of these 2 processes offers promising new therapeutic options for patients who suffer from chronic, nonhealing ischemic wounds. The authors review the current literature on the processes of angiogenesis and vasculogenesis and how it relates to wound healing.
Get full access to this article
View all access options for this article.
References
1.
Harry LE, Paleolog EM: From the cradle to the clinic: VEGF in developmental, physiological, and pathological angiogenesis. Birth Defects Res Part C Embryo Today69:363-374, 2003.
2.
Liu ZJ, Snyder R, Soma A, et al: VEGF-A and alphaVbeta3 integrin synergistically rescue angiogenesis via N-Ras and PI3-K signaling in human microvascular endothelial cells. Faseb J17:1931-1933, 2003.
3.
Djonov V, Baum O, Burri PH: Vascular remodeling by intussusceptive angiogenesis. Cell Tissue Res314:107-117, 2003.
4.
Patan S: Vasculogenesis and angiogenesis. Cancer Treat Res117:3-32, 2004.
5.
Parker TA, le Cras TD, Kinsella JP, et al: Developmental changes in endothelial nitric oxide synthase expression and activity in ovine fetal lung. Am J Physiol Lung Cell Mol Physiol278:L202-L208, 2000.
6.
Reyes M, Dudek A, Jahagirdar B, et al: Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest109:337-346, 2002.
7.
Nakul-Aquaronne D, Bayle J, Frelin C: Coexpression of endothelial markers and CD14 by cytokine mobilized CD34+ cells under angiogenic stimulation. Cardiovasc Res57:816-823, 2003.
8.
Buschmann I, Katzer E, Bode C: Arteriogenesis — is this terminology necessary?Basic Res Cardiol98:1-5, 2003.
9.
Carmeliet P: Angiogenesis in health and disease. Nat Med9:653-660, 2003.
10.
Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med9:669-676, 2003.
11.
Velazquez OC, Herlyn M: The vascular phenotype of melanoma metastasis. Clin Exp Metastasis20:229-235, 2003.
12.
Velazquez OC, Snyder R, Liu ZJ, et al: Fibroblast-dependent differentiation of human microvascular endothelial cells into capillary-like 3-dimensional networks. Faseb J16:1316-1318, 2002.
13.
Sephel GC, Kennedy R, Kudravi S: Expression of capillary basement membrane components during sequential phases of wound angiogenesis. Matrix Biol15:263-279, 1996.
14.
Burbridge MF, Coge F, Galizzi JP, et al: The role of the matrix metalloproteinases during in vitro vessel formation. Angiogenesis5:215-226, 2002.
15.
Giambernardi TA, Grant GM, Taylor GP, et al: Overview of matrix metalloproteinase expression in cultured human cells. Matrix Biol16:483-496, 1998.
Brooks PC, Clark RA, Cheresh DA: Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science264:569-571, 1994.
18.
Hynes RO, Bader BL, Hodivala-Dilke K: Integrins in vascular development. Braz J Med Biol Res32:501-510, 1999.
19.
Le Gat L, Gogat K, Van Den Berghe L, et al: The beta3 integrin gene is expressed at high levels in the major haematopoietic and lymphoid organs, vascular system, and skeleton during mouse embryo development. Cell Commun Adhes10:129-140, 2003.
20.
Jain RK: Molecular regulation of vessel maturation. Nat Med9:685-693, 2003.
21.
Distler JH, Hirth A, Kurowska-Stolarska M, et al: Angiogenic and angiostatic factors in the molecular control of angiogenesis. Q J Nucl Med47:149-161, 2003.
22.
Mallery SR, Lantry LE, Laufman HB, et al: Modulation of human microvascular endothelial cell bioenergetic status and glutathione levels during proliferative and differentiated growth. J Cell Biochem53:360-372, 1993.
23.
Chinoy MR, Graybill MM, Miller SA, et al: Angiopoietin-1 and VEGF in vascular development and angiogenesis in hypoplastic lungs. Am J Physiol Lung Cell Mol Physiol283:L60-L66, 2002.
24.
Gerhardt H, Golding M, Fruttiger M, et al: VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol161:1163-1177, 2003.
25.
Zippo A, De Robertis A, Bardelli M, et al: Identification of Flk-1-target genes in vasculogenesis: Pim-1 is required for endothelial and mural cell differentiation in vitro. Blood103:436-444, 2004.
26.
Luttun A, Tjwa M, Moons L, et al: Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med8:831-840, 2002.
27.
Heissig B, Werb Z, Rafii S, et al: Role of c-kit/Kit ligand signaling in regulating vasculogenesis. Thromb Haemost90:570-576, 2003.
28.
Demir R, Kayisli UA, Seval Y, et al: Sequential expression of VEGF and its receptors in human placental villi during very early pregnancy: Differences between placental vasculogenesis and angiogenesis. Placenta25:560-572, 2004.
29.
Ober EA, Olofsson B, Makinen T, et al: Vegfc is required for vascular development and endoderm morphogenesis in zebrafish. EMBO Rep5:78-84, 2004.
30.
Ferrara N: Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int56:794-814, 1999.
31.
Carmeliet P: Mechanisms of angiogenesis and arteriogenesis. Nat Med6:389-395, 2000.
Bellomo M, Adamo EB, Deodato B, et al: Enhancement of expression of vascular endothelial growth factor after adeno-associated virus gene transfer is associated with improvement of brain ischemia injury in the gerbil. Pharmacol Res48:309-317, 2003.
34.
Bellomo D, Headrick JP, Silins GU, et al: Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ Res86:E29-E35, 2000.
35.
Dumont DJ, Jussila L, Taipale J, et al: Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science282:946-949, 1998.
36.
Chavakis E, Aicher A, Heeschen C, et al: Role of beta2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med201:63-72, 2005.
37.
Tang DG, Conti CJ: Endothelial cell development, vasculogenesis, angiogenesis, and tumor neovascularization: An update. Semin Thromb Hemost30: 109-117, 2004.
38.
Jackson KA, Majka SM, Wang H, et al: Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest107:1395-1402, 2001.
39.
Asahara T, Masuda H, Takahashi T, et al: Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res85:221-228, 1999.
40.
Asahara T, Murohara T, Sullivan A, et al: Isolation of putative progenitor endothelial cells for angiogenesis. Science275:964-967, 1997.
41.
Baksh D, Davies JE, Zandstra PW: Adult human bone marrow-derived mesenchymal progenitor cells are capable of adhesion-independent survival and expansion. Exp Hematol31:723-732, 2003.
42.
Yin AH, Miraglia S, Zanjani ED, et al: AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood90:5002-5012, 1997.
43.
Jiang Y, Jahagirdar BN, Reinhardt RL, et al: Pluripotency of mesenchymal stem cells derived from adult marrow. Nature418:41-49, 2002.
44.
Rafii S, Avecilla S, Shmelkov S, et al: Angiogenic factors reconstitute hematopoiesis by recruiting stem cells from bone marrow microenvironment. Ann NY Acad Sci996:49-60, 2003.
Janowska-Wieczorek A, Marquez LA, Nabholtz JM, et al: Growth factors and cytokines upregulate gelatinase expression in bone marrow CD34(+) cells and their transmigration through reconstituted basement membrane. Blood93:3379-3390, 1999.
47.
Cheng T, Rodrigues N, Shen H, et al: Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science287:1804-1808, 2000.
48.
Huang EJ, Nocka KH, Buck J, et al: Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2. Mol Biol Cell3:349-362, 1992.
49.
Gill M, Dias S, Hattori K, et al: Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res88:167-174, 2001.
50.
Bauer SM, Bauer RJ, Liu ZJ, et al: Vascular endothelial growth factor-C promotes vasculogenesis, angiogenesis, and collagen constriction in three-dimensional collagen gels. J Vasc Surg2005 (in press).
51.
Bergers G, Brekken R, McMahon G, et al: Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol2:737-744, 2000.
52.
Hattori K, Heissig B, Wu Y, et al: Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med8:841-849, 2002.
53.
Bompais H, Chagraoui J, Canron X, et al: Human endothelial cells derived from circulating progenitors display specific functional properties compared with mature vessel wall endothelial cells. Blood103:2577-2584, 2004.
54.
Hristov M, Erl W, Weber PC: Endothelial progenitor cells: Isolation and characterization. Trends Cardiovasc Med13:201-206, 2003.
55.
Pesce M, Orlandi A, Iachininoto MG, et al: Myoendothelial differentiation of human umbilical cord blood-derived stem cells in ischemic limb tissues. Circ Res93:e51-62, 2003.
56.
Hill JM, Zalos G, Halcox JP, et al: Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med348:593-600, 2003.
57.
George J, Goldstein E, Abashidze S, et al: Circulating endothelial progenitor cells in patients with unstable angina: Association with systemic inflammation. Eur Heart J25:1003-1008, 2004.
58.
Diegelmann RF, Evans MC: Wound healing: An overview of acute, fibrotic and delayed healing. Front Biosci9:283-289, 2004.
59.
Goldman R: Growth factors and chronic wound healing: Past, present, and future. Adv Skin Wound Care17:24-35, 2004.
60.
O'Leary R, Rerek M, Wood EJ: Fucoidan modulates the effect of transforming growth factor (TGF)-beta1 on fibroblast proliferation and wound repopulation in in vitro models of dermal wound repair. Biol Pharm Bull27:266-270, 2004.
61.
Yang GP, Lim IJ, Phan TT, et al: From scarless fetal wounds to keloids: Molecular studies in wound healing. Wound Repair Regen11:411-418, 2003.
62.
Mulder GD: Diabetic foot ulcers: Old problems — new technologies. Nephrol Dial Transplant16:695-698, 2001.
63.
Falanga V: The chronic wound: Impaired healing and solutions in the context of wound bed preparation. Blood Cells Mol Dis32:88-94, 2004.
64.
Duckworth WC, Fawcett J, Reddy S, et al: Insulin-degrading activity in wound fluid. J Clin Endocrinol Metab89:847-851, 2004.
65.
Lerman OZ, Galiano RD, Armour M, et al: Cellular dysfunction in the diabetic fibroblast: Impairment in migration, vascular endothelial growth factor production, and response to hypoxia. Am J Pathol162:303-312, 2003.
66.
Wall SJ, Sampson MJ, Levell N, et al: Elevated matrix metalloproteinase-2 and 3 production from human diabetic dermal fibroblasts. Br J Dermatol149:13-16, 2003.
67.
Crovetti G, Martinelli G, Issi M, et al: Platelet gel for healing cutaneous chronic wounds. Transfus Apheresis Sci30:145-151, 2004.
68.
Tateishi-Yuyama E, Matsubara H, Murohara T, et al: Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: A pilot study and a randomised controlled trial. Lancet360:427-435, 2002.