Signaling Pathways in Angiogenesis: Intracrine VEGF Signaling and Vascular Homeostasis

Tumor angiogenesis is a complex, multifactorial phenomenon involving signals from tumor cells and from the responsive host tissue. Our laboratory has been interested in understanding the contribution of VEGF signaling within the endothelial cell compartment itself and have uncovered that intracrine activation of VEGFR2 is relevant to endothelial cell survival under no pathological conditions. Using a Cre‐lox approach in mice, we deleted VEGF from the endothelial lineage. Surprisingly, inactivation of the VEGF gene selectively in endothelial cells results in significant lethality both intraembryonic and in the adult. Survival analysis of a large cohort of mice indicate that 55% of the VEGF‐ECKO die by 24weeks mostly from cardiac infarction. Systemic assessment of the vasculature reveals endothelial cell apoptosis and development of intravascular thrombi. To gain further mechanistic insights and explain the susceptibility to apoptosis displayed by endothelial cells from VEGF‐ECKO mice, we performed a series of signaling experiments. Results from these experiments revealed the existence of an intracrine signaling loop, whereby VEGFR2 is activated by VEGF intracellularly in response to stress‐induced signals. These findings indicate that the VEGF signaling pathway is required to provide survival cues to the vasculature under homeostatic conditions and caution against systemic long‐term suppression of VEGFR2 signaling.