TRPV4 channels mediate cyclic strain-induced endothelial cell reorientation through integrin-to-integrin signaling. Circ Res 2009 May 08;104(9):1123-30
Date
04/11/2009Pubmed ID
19359599Pubmed Central ID
PMC2754067DOI
10.1161/CIRCRESAHA.108.192930Scopus ID
2-s2.0-66149088448 (requires institutional sign-in at Scopus site) 294 CitationsAbstract
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.
Author List
Thodeti CK, Matthews B, Ravi A, Mammoto A, Ghosh K, Bracha AL, Ingber DEAuthor
Akiko Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCapillaries
Cattle
Cell Adhesion
Cell Polarity
Cells, Cultured
Endothelial Cells
Fibronectins
Humans
Integrin beta1
Mechanotransduction, Cellular
Phosphatidylinositol 3-Kinases
RNA Interference
RNA, Small Interfering
Recombinant Fusion Proteins
Stress, Mechanical
TRPV Cation Channels