A new paradigm for vascular endothelial cell growth factor receptor signaling in adult endothelium

The primary role of the endometrium is the cyclical generation of a receptive uterine lining for the successful implantation of a fertilized ovum, a process that is dependent on the growth of new blood vessels. Outside of the female reproductive tract, the majority of the adult vasculature is quiescent and angiogenesis occurs only as part of the body's repair processes or in diseases including diabetic retinopathy, rheumatoid arthritis, atherosclerosis, and cancer. The cellular localization of several angiogenic factors has been described in the endometrium, although their precise biological roles in normal cycling endometrium and endometrial pathologies, such as endometriosis and endometrial cancer, has yet to be established. However, it is clear that vascular endothelial cell growth factor (VEGF) is central to the pathophysiological angiogenesis occurring in the endometrium. VEGF elicits its cellular responses via two high-affinity tyrosine kinase receptors, namely VEGFR-I and VEGFR-2. Until recently, it was presumed that the majority of cellular effects induced by VEGF were mediated by VEGFR-2, whereas VEGFR-1 acted as a decoy. However, results from our laboratory and others have identified VEGFR-1 as an important mediator of VEGF signaling during angiogenesis in the adult. We have shown that activation of VEGFR-I leads to the generation of nitric oxide, which acts as a cue for the negative regulation of VEGFR-2-dependent proliferation and promotes endothelial cell reorganization into three-dimensional vessel networks.