Survival Mechanisms of VEGF and PlGF during Microvascular Remodeling

Angiogenesis, the formation of new blood vessels frompreexisting vessels, is a complex and tightly regulatedprocess involving endothelial cell migration, proliferation, and survival. The roles of endothelial cell migrationand proliferation have been well established; however,the role of survival has only recently been recognized.Many mediators of vascular development have beenidentified and include growth factors, cytokines, membrane-bound molecules, and hemodynamic forces. Theyall play important roles during development, elicitingunique changes in a spatial and temporal manner. Severalof them have also been shown to influence endothelialcell survival, and the signals they induce tend to overlap,thus assuring the survival of endothelial cells under a variety of adverse conditions. The importance of having acoordinated regulation between survival and apoptosiscannot be overemphasized. Survival selects desirablecells and maintains cell number, while apoptosis eliminates abnormal, misplaced, or nonfunctional cells; decreases cell number; and removes vestigial structures (Jacobson et al. 1997). Coordination of these processescontributes to the structural remodeling that occurs in every organ. It is particularly important for vascular development and constitutes a major aspect of angiogenesis.Disruption in either the survival signaling pathway, suchas loss of the vascular endothelial growth factor gene(Carmeliet et al. 1996; Ferrara et al. 1996), or the programmed cell death pathway, such as loss of the caspase-3 gene (Kuida et al. 1996), is associated with increasedmorbidity and mortality. Moreover, unchecked vasculargrowth leads to cardiovascular defects and vascular neoplasms, whereas increased apoptosis causes embryonaldeath, hemorrhage, and vascular defects (Pietsch et al.1997; Gerber et al. 1999; Fisher et al. 2000)...