ABSTRACT
It has been well documented that the development of a collateral circulation can attenuate tissue ischemia in peripheral and coronary artery diseases. The classic mechanism of postnatal neovascularization had been considered to be limited to angiogenesis, i.e. proliferation and migration of pre-existing mature endothelial cells (ECs). Therefore, approaches by which one may augment collateral circulation in ischemic diseases in preclinical and clinical studies have been referred to as ‘therapeutic angiogenesis’. Gene transfer of angiogenic growth factors, for example, has been reported to attenuate tissue ischemia through stimulation of angiogenesis at sites of neovascularization.1-4
Vasculogenesis, which indicates incorporation of circulating endothelial progenitor cells (EPCs) into foci of neovascularization and their proliferation, migration and differentiation into mature ECs, was believed to occur only during embryonic neovascularization, until postnatal vasculogenesis was first reported in 1997.5 Our laboratory demonstrated that EPCs are mobilized from bone marrow into the circulation in response to tissue ischemia.6 In addition to the mobilization of intrinsic EPCs in ischemic diseases, we have also reported that intravenous transplantation of exogenous EPCs, isolated as CD34+ cells from adult peripheral blood, results in the incorporation of the EPCs into foci of neovascularization of hindlimb ischemia.5 These findings encouraged the therapeutic use of EPCs to augment collateral formation in ischemic diseases. On the other hand, administration of vascular endothelial growth factor (VEGF) was shown to increase the number of differentiated EPCs in vitro and to augment corneal neovascularization in vivo.7 Recently, a pilot clinical study confirmed a similar beneficial effect of VEGF gene transfer in human patients. The number of circulating EPCs increased following VEGF gene transfer in patients with critical limb ischemia.8 These findings suggest that vasculogenesis may be a key
component in what was previously termed therapeutic angiogenesis. Thus, discerning the role of vasculogenesis in the pathophysiology and therapeutic neovascularization of ischemic diseases is now recognized as essential.
