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.
Wu
Jianqiang
J
Department of Ophthalmology, University of Wisconsin Medical School, Madison, Wisconsin 53792, USA.
Sheibani
Nader
N
D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002465:Cell Movement; D048429:Cell Size; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism; D014638:Vanadates / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D003094:Collagen; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D020928:Mitogen-Activated Protein Kinases; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011509:Proteoglycans; D013755:Tetradecanoylphorbol Acetate; D019700:Thrombospondin 1; D014638:Vanadates; D019061:src-Family Kinases; D000099152:Cadherin 5; C076715:pervanadate; C059485:matrigel