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(Circulation. 2002;105:2133.)
© 2002 American Heart Association, Inc.

Editorial

Nitric Oxide and Angiogenesis

John P. Cooke, MD, PhD; Douglas W. Losordo, MD

From the Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif.

Correspondence to John P. Cooke, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5406. E-mail john.cooke@stanford.edu

Key Words: Editorials • nitric oxide • endothelium • angiogenesis • growth substances

Endothelium-derived nitric oxide (NO) is a mediator of angiogenesis. Vascular endothelial growth factor (VEGF) stimulates the release of NO from cultured human umbilical venous endothelial cells and upregulates the expression of nitric oxide synthase (NOS).^1,2 Segments of rabbit thoracic aorta release NO in response to VEGF; preincubation with L-arginine increases basal and VEGF-stimulated NO release 2-fold.² Similar results are observed when the angiogenic stimulus is transforming growth factor ß or basic fibroblast growth factor.^3–5

See p 2185

The release of NO by these factors plays a critical role in their angiogenic actions. In a 3D fibrin gel, human umbilical venous endothelial cells elaborate NO and form capillary-like structures when stimulated by basic fibroblast growth factor or VEGF, effects that are blocked by the NOS antagonist N^w-nitro-L-arginine methyl ester (L-NAME).^6,7 Similar effects have been observed in vitro using substance P or transforming growth factor ß.^8,9 In the rabbit cornea model of angiogenesis, VEGF-induced angiogenesis is antagonized by L-NAME.¹⁰

Angiogenesis is attenuated when NO bioactivity is reduced. Capillary-like outgrowths sprout from segments of rabbit thoracic aorta or human coronary artery explanted into a collagen matrix. This ex vivo angiogenesis is inhibited by oxidized LDL cholesterol,^11,12 an agent also known to reduce NO bioactivity. In hypercholesterolemic rabbits, endothelium-dependent NO-mediated vasodilation is blunted, as is the angiogenic response to hindlimb ischemia.¹³ More definitively, the angiogenic response to hindlimb ischemia is impaired in the eNOS-deficient mice, an effect that cannot be reversed by administration of recombinant VEGF protein or adenovirus-mediated VEGF . . . [Full Text of this Article]

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