TRPV4 channels mediate cyclic strain-induced endothelial cell reorientation through integrin-to-integrin signaling.
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 beta1 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.
Vascular Biology Program, Department of Surgery, 300 Longwood Avenue, Children's Hospital/Harvard Medical School, Boston, MA 02115, USA.
Charles K
CK
Thodeti
Benjamin
B
Matthews
Arvind
A
Ravi
Akiko
A
Mammoto
Kaustabh
K
Ghosh
Abigail L
AL
Bracha
Donald E
DE
Ingber
D000818:Animals; D002196:Capillaries / Q000378:metabolism; D002417:Cattle; D002448:Cell Adhesion; D016764:Cell Polarity; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D040542:Mechanotransduction, Cellular; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013314:Stress, Mechanical; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
D005353:Fibronectins; D019012:Integrin beta1; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D019869:Phosphatidylinositol 3-Kinases