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Ann Thorac Surg 2002;73:824
© 2002 The Society of Thoracic Surgeons
a Cardiac Physiology Laboratory, Divisions of Circulatory Physiology and Cardiology, Columbia University, 650 W 168th St, New York, NY 10032, USA
In this article, Dr Liu and colleagues demonstrate the vasodilating effects of vascular endothelial growth factor (VEGF, also known as vascular permeability factor) on isolated internal mammary artery vascular rings. It is further demonstrated that this relaxation is endothelium-dependent and is mediated by nitric oxide (NO). This study reports important confirmatory data of prior studies. Vasodilatory actions of VEGF have been demonstrated previously in animal and human endothelium and this has been demonstrated to be dependent upon NO release [1]. The mechanism by which VEGF induces endothelial NO production involves a reasonably well characterized signaling cascade. VEGF binding to the Flk-1/KDR receptor induces phosphorylation of Akt [2] which in turn phosphorylates endothelial NO synthase (eNOS), enhancing its ability to generate NO [3]. Importantly, increased NO release is also believed to fundamentally contribute to the angiogenic effects of VEGF [4].
Local myocardial vasodilation in the heart could help enhance blood flow to treated areas independent of new blood vessel growth, though this effect would be expected to be short lived, being confined to the time period of increased local VEGF concentration. On the other hand, this effect of VEGF has been considered to be responsible for systemic hypotension seen following VEGF injections in animals [5, 6] and man [7].
Several strategies to achieve therapeutic angiogenesis using VEGF genes or proteins, as well as other growth factors, are in various stages of investigation. With the exception of small feasibility studies, larger scale multicenter studies have not yet indicated which, if any, strategy will provide a successful angiogenic therapy. For peripheral vascular disease, bFGF treatment appears promising [8]. Although still preliminary, the safety profile of these agents, including VEGF, appears to be acceptable in a variety of settings [9]. This includes the hypotensive side effects.
Thus, the vasodilator effects of VEGF may provide an added potential benefit on local myocardial perfusion above and beyond its potential to enhance angiogenesis. It is important that the systemic effects of VEGF be investigated, though preliminary results indicate that this is not a limiting factor, especially when delivered locally to the heart as a gene product. It is only through careful studies such as those of Dr Liu and colleagues which increase our understanding of the actions and mechanisms of growth factors such as VEGF that the promise of therapeutic angiogenesis can be realized.
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