Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease

Abstract

### Endothelial Progenitor Cells and Postnatal Vasculogenesis: Experimental Evidence The option of performing full-scale endothelial cell transplantation to optimize local neovascularization is daunting if even feasible. An alternative, attractive strategy is designed to exploit the conceptual notion that endothelial cells and hematopoietic stem cells were ultimately derived from a common precursor, the putative hemangioblast. Hematopoietic stem cells had been shown previously to be present in circulating blood, in quantities sufficient to permit their harvesting and readministration for autologous, in lieu of bone marrow, transplantation. The related descendants, endothelial progenitor cells, can be detected in the peripheral circulation.1,2 Initially, Flk-1 and a second antigen, CD34, shared by angioblasts and hematopoietic stem cells were used to isolate putative angioblasts from the leukocyte fraction of peripheral blood.1 Meanwhile, endothelial progenitor cells were isolated from human umbilical cord blood,3 bone marrow–derived mononuclear cells,4 and CD34+ or CD133+ hematopoietic stem cells1,5 and were successfully ex vivo expanded with the use of human peripheral blood mononuclear cells.6 These cells differentiated into endothelial cells, as shown by expression of various endothelial proteins (KDR, von Willebrand factor, endothelial nitric oxide synthase, VE-cadherin, CD146) and uptake of Dil-acetylated LDL and binding of lectin.1,7 In animal models of ischemia, heterologous, homologous, and autologous endothelial progenitor cells were shown to incorporate into sites of active neovascularization in ischemic and tumor tissue. Blood flow recovery and capillary density were markedly improved, and the rate of limb loss was significantly reduced after transplantation of human peripheral blood–derived endothelial progenitor cells8,9 or bone marrow mononuclear cells.10 Likewise, infusion of peripheral blood–derived endothelial progenitor cells,11 bone marrow mononuclear cells,12 or purified CD34+ cells13 improved neovascularization and myocardial function after infarction. Isolated CD34+ cells also increased impaired blood flow in diabetic mice.14 These findings provide evidence that exogenously …