A mechanosensory complex that mediates the endothelial cell response to fluid shear stress.
Shear stress is a fundamental determinant of vascular homeostasis, regulating vascular remodelling, cardiac development and atherogenesis, but the mechanisms of transduction are poorly understood. Previous work showed that the conversion of integrins to a high-affinity state mediates a subset of shear responses, including cell alignment and gene expression. Here we investigate the pathway upstream of integrin activation. PECAM-1 (which directly transmits mechanical force), vascular endothelial cell cadherin (which functions as an adaptor) and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) comprise a mechanosensory complex. Together, these receptors are sufficient to confer responsiveness to flow in heterologous cells. In support of the relevance of this pathway in vivo, PECAM-1-knockout mice do not activate NF-kappaB and downstream inflammatory genes in regions of disturbed flow. Therefore, this mechanosensing pathway is required for the earliest-known events in atherogenesis.
Tzima
Eleni
E
Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Irani-Tehrani
Mohamed
M
Kiosses
William B
WB
Dejana
Elizabetta
E
Schultz
David A
DA
Engelhardt
Britta
B
Cao
Gaoyuan
G
DeLisser
Horace
H
Schwartz
Martin Alexander
MA
D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002417:Cattle; D002448:Cell Adhesion; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013314:Stress, Mechanical; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5