Modulation of VE‐cadherin and PECAM‐1 mediated cell–cell adhesions by mitogen‐activated protein kinases

Endothelial cell transition from a differentiated, quiescent phenotype to a migratory, proliferative phenotype is essential during angiogenesis. This transition is dependent on alterations in the balanced production of stimulatory and inhibitory factors, which normally keep angiogenesis in check. Activation of MAPK/ERKs is essential for endothelial cell migration and proliferation. However, its role in regulation of endothelial cell adhesive mechanisms requires further delineation. Here, we show that sustained activation of MAPK/ERKs results in disruption of cadherin‐mediated cell–cell adhesion, down‐regulation of PECAM‐1 expression, and enhanced cell migration in microvascular endothelial cells. Expression of a constitutively active MEK‐1 in mouse brain endothelial (bEND) cells resulted in down‐regulation of VE‐cadherin and catenins expression concomitant with down‐regulation of PECAM‐1 expression. In contrast, inhibition of MEK‐1 restored parental morphology, cadherin/catenins expression and localization. These data are further supported by our observation that sustained activation of MAPK/ERKs in phorbol myristate acetate incubated HUVEC lead to disruption of cadherin‐mediate cell–cell interactions and enhanced capillary formation on Matrigel. Thus, sustained activation of MAPK/ERKs plays an important role in disruption of cell–cell adhesion and migration of endothelial cells. J. Cell. Biochem. 90: 121–137, 2003. © 2003 Wiley‐Liss, Inc.

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