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Stress‐activated TRPV4 channels mediate integrin to integrin mechanical signaling that is required for angiogenesis
Author(s) -
Thodeti Charles K,
Ingber Donald E.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.464.12
Subject(s) - angiogenesis , integrin , microbiology and biotechnology , mechanotransduction , chemistry , extracellular matrix , focal adhesion , signal transduction , small interfering rna , receptor , biology , biochemistry , cancer research , transfection , gene
Physical forces applied to extracellular matrix (ECM) influence the direction of capillary endothelial cell outgrowth during angiogenesis, but little is known about how capillary cells sense and transduce mechanical signals responsible for these spatially oriented responses. Here we show that capillary cells reorient perpendicular to the direction of the applied force when cyclic mechanical strain is exerted on their integrin‐ECM adhesions, and that this results from activation of a mechanical signaling pathway that induces calcium influx through stress‐activated TRPV4 ion channels that, in turn, stimulates phosphatidyl inositol‐3‐kinase, thereby inducing activation and binding of additional β1 integrin receptors that promotes Rho‐dependent cytoskeletal remodeling. Moreover, knockdown of TRPV4 channels using specific siRNA inhibits angiogenesis in vitro, whereas control siRNAs have no effect on capillary formation. Thus, physical forces may guide angiogenesis through an “integrin to integrin” signaling mechanism that is mediated by stress‐induced activation of mechanically‐gated TRPV4 ion channels on the cell surface. (Supported by NIH and AHA)