Reciprocal role of vasculogenic factors and progenitor cells in atherogenesis.

While neovascularization plays an integral role in atherosclerosis, stimulation of angiogenesis does not appear to promote atherogenesis. This observation is important in view of recent advancements in angiogenic gene and cell therapy aimed at promoting new blood vessel growth in humans with vascular disease. Endothelial progenitor cells (EPCs) may actually prevent rather than provoke intimal thickening and vascular remodeling by promoting re-endothelialization in response to vascular trauma, as occurs with percutaneous transluminal vascular intervention for treating atherosclerotic vessels. Further support for the hypothesis that EPCs continuously repair vascular injury and contribute to the rejuvenation of vessels has been derived from animal studies demonstrating that serial injection of bone marrow-derived EPCs prevent atherogenesis, but that the quantity and quality of these cells deteriorate with aging. This chapter provides a summary of the influence of angiogenesis on atheromatous disease. Furthermore, the increasingly important relationship between atherosclerosis and newly emerging techniques in therapeutic angiogenesis (i.e., gene therapy and cell therapy with EPCs) is discussed.

Vascular endothelial growth factor(165) gene transfer augments circulating endothelial progenitor cells in human subjects.

Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs). In patients with critical limb ischemia receiving VEGF gene transfer, gene expression was documented by a transient increase in plasma levels of VEGF. A culture assay documented a significant increase in EPCs (219%, P<0.001), whereas patients who received an empty vector had no change in circulating EPCs, as was the case for volunteers who received saline injections (VEGF versus empty vector, P<0.001; VEGF versus saline, P<0.005). Fluorescence-activated cell sorter analysis disclosed an overall increase of up to 30-fold in endothelial lineage markers KDR (VEGF receptor-2), VE-cadherin, CD34, alpha(v)beta(3), and E-selectin after VEGF gene transfer. Constitutive overexpression of VEGF in patients with limb ischemia augments the population of circulating EPCs. These findings support the notion that neovascularization of human ischemic tissues after angiogenic growth factor therapy is not limited to angiogenesis but involves circulating endothelial precursors that may home to ischemic foci and differentiate in situ through a process of vasculogenesis.