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(Circulation Research. 2009;104:1123.)
© 2009 American Heart Association, Inc.

Cellular Biology

TRPV4 Channels Mediate Cyclic Strain–Induced Endothelial Cell Reorientation Through Integrin-to-Integrin Signaling

Charles K. Thodeti, Benjamin Matthews, Arvind Ravi, Akiko Mammoto, Kaustabh Ghosh, Abigail L. Bracha, Donald E. Ingber

From the Vascular Biology Program (C.K.T., B.M., A.R., A.M., K.G., A.L.B., D.E.I.) and Departments of Pathology (D.E.I.), Surgery (C.K.T., B.M., A.M., K.G., D.E.I.), and Medicine (B.M.), Harvard Medical School and Children’s Hospital, Boston; and Wyss Institute for Biologically Inspired Engineering and Harvard School of Engineering and Applied Sciences (D.E.I.), Cambridge, Mass.

Correspondence to Donald E. Ingber, MD, PhD, Vascular Biology Program, KFRL 11.127,300 Longwood Ave, Children’s Hospital/Harvard Medical School, Boston, MA 02115. E-mail donald.ingber{at}childrens.harvard.edu

Cyclic mechanical strain produced by pulsatile blood flow regulates the orientation of endothelial cells lining blood vessels and influences critical processes such as angiogenesis. Mechanical stimulation of stretch-activated calcium channels is known to mediate this reorientation response; however, the molecular basis remains unknown. Here, we show that cyclically stretching capillary endothelial cells adherent to flexible extracellular matrix substrates activates mechanosensitive TRPV4 (transient receptor potential vanilloid 4) ion channels that, in turn, stimulate phosphatidylinositol 3-kinase–dependent activation and binding of additional β1 integrin receptors, which promotes cytoskeletal remodeling and cell reorientation. Inhibition of integrin activation using blocking antibodies and knock down of TRPV4 channels using specific small interfering RNA suppress strain-induced capillary cell reorientation. Thus, mechanical forces that physically deform extracellular matrix may guide capillary cell reorientation through a strain-dependent "integrin-to-integrin" signaling mechanism mediated by force-induced activation of mechanically gated TRPV4 ion channels on the cell surface.

Key Words: mechanical strain • integrin • TRPV4 • endothelial cell • reorientation • cytoskeleton