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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1462.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Arteriolar Genesis and Angiogenesis Induced by Endothelial Nitric Oxide Synthase Overexpression Results in a Mature Vasculature

Andrew V. Benest; Oliver A. Stone; William H. Miller; Colin P. Glover; James B. Uney; Andrew H. Baker; Steven J. Harper; David O. Bates

From Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology (A.V.B., O.A.S., S.J.H., D.O.B.) and Laboratories for Integrative Neuroscience and Endocrinology (C.P.G., J.B.U.), University of Bristol, and BHF Glasgow Cardiovascular Research Centre (W.H.M., A.H.B.), University of Glasgow, UK. Present address for A.V.B.: Division of Vascular Oncology and Metastasis A190, DKFZ, Im Neuenheimer Feld 581 (TP4), D-69120 Heidelberg, Germany.

Correspondence to Dr David Bates, Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology, University of Bristol, Southwell Street, Bristol BS2 8EJ United Kingdom. E-mail dave.bates{at}bristol.ac.uk

Background— Generation of physiologically active vascular beds by delivery of combinations of growth factors offers promise for vascular gene therapy.

Methods and 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.

Conclusion— 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.

Generation of contractile microvessels (arteriogenesis) is required for the development of therapeutic angiogenic strategies. Here we show that this can be achieved by combining growth factors (VEGF and Ang1) with vasodilators (eNOS overexpression or prazosin), providing an additional strategy for neovascular gene therapy.

Key Words: angiogenesis • arteriogenesis • VEGF • Ang-1 • eNOS • pericyte • vascular smooth muscle