Control of Vascular Homeostasis by VE-PTP and VE-cadherin

The vascular endothelium undergoes tightly regulated and dynamic remodeling throughout life. A host of intracellular factors and environmental cues regulate vascular integrity to balance fluid and cellular transport between the vascular lumen and underlying tissues and organs. Modulation of endothelial barrier function is critical for angiogenesis, immune system function, and blood pressure maintenance, while defects promote pathological conditions including sepsis, ischemia, edema, and inflammation. Thus, research focused on evolving a fundamental understanding of this highly dynamic and critical system will have broad implications for human health.

The endothelial specific VEGFR2 and Tie2 signaling pathways inversely regulate endothelial barrier function through direct modulation of VE-cadherin, a cell adhesion receptor and major component of adherens junctions. The vascular permeability effects of VEGF, for example, are regulated, at least in part, by the src-mediated phosphorylation of the VE-cadherin cytoplasmic tail resulting in release of the cadherin binding proteins plakoglobin or β-catenin. Similarly, p120 binding to VE-cadherin is required for accurate targeting and maintenance of VE-cadherin at the cell membrane and phosphorylation of p120 results in VE-cadherin internalization. In contrast, the anti-permeability factor Ang-1 stimulates VE-cadherin dephosphorylation and stabilization of the endothelial barrier via a largely uncharacterized receptor tyrosine phosphatase, vascular endothelial protein tyrosine phosphatase (VE-PTP). Interestingly, Tie2 activity (in response to Ang-1) is itself regulated by VE-PTP suggesting that at the endothelial membrane a negative feedback loop operates between Tie2, VE-PTP, and VE-cadherin. Therefore, a balance of kinase (phosphorylation) and phosphatase (dephosphorylation) activities appears to at least partially regulate endothelial cellular adhesion and, therefore, vascular integrity through VE-cadherin.

Functional cross-talk between VE-PTP, VE-cadherin, and Tie2 signaling pathways is essential to coordinate endothelial cell adhesion and is highlighted by the observation that their respective knock-out mice display similar phenotypes. Indeed, VE-PTP, VE-cadherin, and Tie2 function is essential for viability and loss of function of any one results in profound defects in angiogenesis and vascular remodeling. Previous studies revealed that Tie2 and VE-cadherin directly associate with VE-PTP through their cytoplasmic and extracellular domains, respectively. Alternatively, we postulate that VE-PTP is indirectly targeted to VE-cadherin by mutual interactions with Tie2. In agreement, we find that VE-PTP and VE-cadherin fail to co-localize in the absence of Tie2 activation suggesting that protein interactions target VE-PTP to its substrates. As a central regulator of vascular integrity, it is critical that we understand how VE-PTP functions at the molecular level to control Tie2 and VE-cadherin signaling pathways. Accordingly, to further explore VE-PTP function, we propose to monitor its association with cellular co-receptors and correlate its activity and interactions with its atomic structure.