Arteriolar genesis and angiogenesis induced by endothelial nitric oxide synthase overexpression results in a mature vasculature.
BACKGROUND
Generation of physiologically active vascular beds by delivery of combinations of growth factors offers promise for vascular gene therapy.


RESULTS
In a mesenteric model of physiological angiogenesis, combining endothelial nitric oxide synthase (eNOS) (and hence NO production) with VEGF and angiopoietin-1 overexpression resulted in a more functional vascular phenotype than growth factor administration alone. eNOS gene delivery upregulated eNOS, VEGF, and Ang-1 to similar levels as gene transfer with VEGF or Ang-1. eNOS overexpression resulted in neovascularization to a similar extent as VEGF and Ang-1 combined, but not by sprouting angiogenesis. Whereas combining Ang-1 and VEGF increased both exchange vessels and conduit vessels, neither growth factor nor eNOS alone resulted in vessels with smooth muscle cell (SMC) coverage. In contrast, combining all three generated microvessels with SMCs (arteriolar genesis) and further increased functional vessels. Use of a vasodilator, prazosin, in combination with Ang1 and VEGF, but not alone, also generated SMC-positive vessels.


CONCLUSIONS
Coexpression of eNOS, VEGF, and Ang-1 results in a more mature vascularization of connective tissue, and generates new arterioles as well as new capillaries, and provides a more physiological therapeutic approach than single growth factor administration, by combining hemodynamic forces with growth factors.
Benest
Andrew V
AV
Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology, University of Bristol, Southwell Street, Bristol BS2 8EJ, United Kingdom.
Stone
Oliver A
OA
Miller
William H
WH
Glover
Colin P
CP
Uney
James B
JB
Baker
Andrew H
AH
Harper
Steven J
SJ
Bates
David O
DO
D042683:Angiopoietin-1 / Q000502:physiology; D000818:Animals; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D020286:Pericytes / Q000502:physiology; D051381:Rats; D012039:Regional Blood Flow / Q000502:physiology; D013152:Splanchnic Circulation / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D042683:Angiopoietin-1; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat