[Signaling mechanism involved in regulation of endothelial cell-cell junctions].
Endothelial cells lining blood vessels are in tight contact with each other, thereby maintaining vascular integrity. Compromising vascular integrity leads to an increase in vascular permeability, which is associated with chronic inflammation, edema, and tumor angiogenesis. Vascular endothelial (VE)-cadherin is an endothelium-specific cell-cell adhesion molecule involved in endothelial barrier functions. We previously reported that cyclic AMP-elevating agonists such as prostaglandins and adrenomedullin potentiate VE-cadherin-dependent cell adhesion by inducing activation of Rap1 small GTPase through Epac. We further investigated the mechanism whereby Rap1 potentiates VE-cadherin-dependent cell adhesion, and found that Rap1 induces the formation of circumferential actin bundles along the cell-cell junctions. Although it has been believed that α-/β-catenins anchor cadherin to the actin cytoskeleton to stabilize cadherin at cell-cell junctions (classical model), Nelson's and Weis' groups have recently suggested a new dynamic model in which α-/β-catenins do not stably connect actin to cadherin. However, our study clearly indicated that the circumferential actin bundles anchor VE-cadherin to the cell-cell junctions through α-/β-catenins. Thus Rap1 potentiates endothelial cell-cell junctions through the mechanism based on the static model.
Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan. fuku@ri.ncvc.go.jp
Shigetomo
S
Fukuhara
Naoki
N
Mochizuki
D000199:Actins / Q000378:metabolism; D042683:Angiopoietin-1 / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism / Q000502:physiology*; D002199:Capillary Permeability; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology; D003599:Cytoskeleton / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D007365:Intercellular Junctions / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051178:alpha Catenin / Q000502:physiology; D051176:beta Catenin / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D000099152:Cadherin 5
D000199:Actins; D042683:Angiopoietin-1; D015703:Antigens, CD; D015820:Cadherins; D015815:Cell Adhesion Molecules; D000242:Cyclic AMP; D051178:alpha Catenin; D051176:beta Catenin; D020827:rap1 GTP-Binding Proteins; D000099152:Cadherin 5