VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization.
There are growing data to suggest that tissue hypoxia represents a critical force that drives adult vasculogenesis. Vascular endothelial growth factor (VEGF) expression is dramatically up-regulated by hypoxia and results in enhanced neovascularization. Although the role of VEGF in angiogenesis has been well characterized, its role in adult vasculogenesis remains poorly understood. We used two distinct murine bone marrow transplantation (BMT) models to demonstrate that increased VEGF levels at the site of tumor growth promoted vasculogenesis in vivo. This effect of VEGF was downstream of its effect to enhance either mobilization or survival of circulating endothelial progenitor cells (EPCs). Both VEGFR1 (flt1) and VEGFR2 (flk1) are expressed on culture expanded human EPCs. Previous studies suggest that the effect of VEGF on endothelial cell migration is primarily mediated via VEGFR2; however, VEGF-induced EPC migration in vitro was mediated by both receptors, suggesting that VEGF-VEGFR1 interactions in EPCs are distinct from differentiated endothelial cells. We used specific blocking antibodies to these receptors to demonstrate that VEGFR1 plays an important role in human EPC recruitment to tumors. These findings were further supported by our finding that tumor-associated placental growth factor (PlGF), a VEGFR1-specific agonist, increased tumor vasculogenesis in a murine BMT model. We further showed that both VEGF receptors were necessary for the formation of functional vessels derived from exogenously administered human ex vivo expanded EPCs. Our data suggest local VEGF and/or PlGF expression promote vasculogenesis; VEGF plays a role in EPC recruitment and subsequent formation of functional vessels.
Li
Bin
B
Department of Pathology, Vanderbilt University School of Medicine, 1161 21st Ave. South, C2217 MCN, Nashville, Tennessee 37232, USA.
Sharpe
Emerson E
EE
Maupin
Amanda B
AB
Teleron
Amylynn A
AA
Pyle
Amy L
AL
Carmeliet
Peter
P
Young
Pampee P
PP
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology; D005966:Glucuronidase / Q000172:deficiency / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000502:physiology*
D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D005966:Glucuronidase