Grant: Operating Grant

Maintenance of endothelial cell integrity represents a very important aspect of normal vascular function. Understanding of mechanisms influencing endothelial cell viability has, therefore, very wide implications to normal vascular biology and pathological conditions of the vasculature. Recent studies have identified the Angiopoietin/Tie-2 receptor system as a major regulator of endothelial cell integrity and survival. This system consists of endothelial cell-specific receptors (Tie-2) and a group of ligands (angiopoietins). Upon Tie-2 receptor activation, endothelial cells undergo several changes designed to enhance angiogenesis. These changes include increased migration, sprouting, adhesion and proliferation. In our previous grant, we have discovered that Mitogen-Activated Protein Kinases (MAPKs) are important signaling pathways through which Tie-2 receptors modulate endothelial cell growth and differentiation. In this proposal, we will investigate who MAPK activity is finely tuned by various signaling pathways. We will first evaluate how the NADPH oxidase regulates individual components of the MAPKs when the Tie-2 receptors are activated. We will then test how MAPK signals that are elicited by Tie-2 receptor activation are being terminated by dual-specificity phosphatases. We will also assess whether MAPKs induce two transcription factors, namely, AP-1 and Nur77 and whether these factors regulate inflammation on endothelial cells. Finally, we will evaluate in the final project whether modification of histones by histone deacetylase 7 is a signal pathways through which Tie-2 receptors modulate endothelial cell survival and angiogenesis responses.