The Regulatory Mechanism Of VE-Cadherin-Mediated Vascular Endothelial Cell Adherens Junctions

VE-cadherin is a keymolecule invascularendothelial cells(ECs) adherens junctions.The abnormality of structure and function of VE-cadherin may result in the dissociation of cell adherens junctions. Recent studies show that the intracellular domain of VE-cadherin also plays a critical role in EC membrane stable distribution of the protein and its adherens junctions, although the intracellular domain of VE-cadherin doesn’t directly participate in the adherens junctions between the ECs.ECs are located at the inner layer of vascular wall and directly contact with various pathological factors, which leads to loss of VE-cadherin stability, endocytosis and a derease in cell adherens junctions. However, the regulatory mechanism is not clear. In addition, how various pathological factors to change VE-cadherin structure and function, to damage EC adherens junctions, and to cause the imbalance of vascular homeostasis are still enigmatic. Thus, it is very urgent to study the regulatory mechanisms of VE-cadherin medicated cell adherens junctions and vascular homeostasis.In our study, we explored the regulatory mechanism of VE-cadherin-mediated EC adherens junctions. Cytological studies reveal that thrombin can cause endothelial cell shrinkage, while cigarette smoking extracts(CSE) cause endothelial cells swelling and decrease in VE-cadherin membrane distribution, resulting in dissociation of EC adherens junctions and increase endothelial permeability.The molecular mechanism studies discover that thrombin and CSE can induce phosphorylation of VE-cadherin at Tyr 731, leading to endocytosis of both VE-cadherin and β-catenin, and dissociation of cell adhesion junctions. DNA microarray analysis displays that CSE can aberrantly up-regulate expression of 645 genes, including various inflammatory and ER stress genes, notably IL-13RA2, IL-1, and DDIT3. Moreover,CSE can activate P38 and CREB signal pathways and inhibit STAT3 signal pathway.In addition, we studied the role of VE-PTP in protection of VE-cadherin and its function in EC adherens junctions. VE-PTP can elevate VE-cadherin protein level,effectively prevent phosphorylation of VE-cadherin at Tyr 731, antagonizingCSE-mediated damage of EC adherens junctions.Taken together, this study reveals that thrombin and CSE can promote phosphorylation of VE-cadherin(Tyr 731), resulting in dissociation of EC adherens junctions. VE-cadherin phosphorylation at Tyr 731 is a key point of the regulatory mechanism of VE-cadherin-mediated cell adherens junctions. Additionally, VE-PTP can effectively reduce the phosphorylation of VE-cadherin at Tyr 731 and enhance VE-cadherin-mediated EC adherens junctions. Thus, our study provides new thoughts for the study of endothelial cell adherens junctions and vascular homeostasis.