Jeffrey M. Isner

Therapeutic Angiogenesis for the Treatment of Cardiovascular Disease

The development of blood vessels may be considered in several contexts. Vasculogenesis and angiogenesis are the processes responsible for the development of the circulatory system, the first functional unit in the developing embryo (1). Pathologic angiogenesis includes the role of post-natal neovascularization in the pathogenesis of arthritis, diabetic retinopathy, and, most notably, tumor growth and metastasis (2). Therapeutic angiogenesis involves the development of collateral blood vessels supplying ischemic tissues, either endogenously or in response to administered growth factors. The purpose of this review is to consider the mechanisms responsible for therapeutic angiogenesis, which develops endogenously, as well as novel strategies, which have been devised to augment this response. Because recapitulation of the embryonic paradigm forms the conceptual basis for therapeutic, as well as pathologic angiogenesis, selected aspects of embryonic blood-vessel development are included. While pathologic angiogenesis is beyond the scope of the current paper, certain principles which have emerged from studies of pathologic neovascularization are considered for the implications they may have for cardiovascular disease.

1012-103 Restoration of Endothelial Function in Hypercholesterolemic Rabbit by Intermittent Administration of Vascular Endothelial Growth Factor

Endothelial dysfunction in hypercholesterolemia causes abnormal arterial vasoreactivity and precedes the onset of atherosclerosis, Vascular endothelial growth factor (VEGF) is an endothelial cell (EC) specific mitogen that has been shown to stimulate EC proliferation in vitro and in vivo. We investigated the hypothesis that VEGF could also modulate EC dysfunction and thereby improve endothelium-dependent vasoreactivity, impaired due to hypercholesterolemia. Hypercholesterolemic rabbits fed a 1% cholesterol diet for 6 weeks were treated with intravenous administration of 300xa0μg VEGF (VEGF group; nxa0=xa08) or 0.9% saline solution (control group; nxa0=xa09) twice a week for 3 weeks, during which time both groups continued to receive cholesterol diet. All rabbits were evaluated by in vivo vasomotion study; 8 normal (non-cholesterol and non-treated) rabbits were evaluated as well. The vasoreactive response to acetylcholine, serotonin and nitroprusside were calculated from flow velocity measured by Doppler wire, vessel diameter obtained from angiograms, and intra-arterial blood pressure recorded at the proximal external iliac artery. The resistance response to endotheliumdependent and -independent agonists recovered in VEGF group, as illustrated below. Furthermore, average intimal thickness of external iliac artery and lower abdominal aorta in VEGF group was significantly less than control group (VEGFxa0=xa00.010xa0±xa00.008 vs controlxa0=xa00,106xa0±xa00.036, Pxa0lxa00,05). Download : Download high-res image (113KB) Download : Download full-size image Conclusion Intermittent systemic administration of VEGF improves endothelial dysfunction and attenuates intimal thickness in hypercholesterolemic rabbit.