© 1997 American Heart Association, Inc.
Articles |
Integrin Signaling Transduces Shear Stress–Dependent Vasodilation of Coronary Arterioles
the Department of Veterinary Biomedical Sciences (J.M.M.), University of Missouri, Columbia; the Department of Physiology (W.M.C.), Medical College of Wisconsin, Milwaukee; and the Microcirculation Research Institute (M.J.D.), Department of Medical Physiology, Texas A&M University Health Science Center, College Station.
Correspondence to Dr William M. Chilian, Department of Physiology, Medical College of Wisconsin, PO Box 26509, 8701 Watertown Plank Rd, Milwaukee, WI 53226-0509. E-mail chilian@post.its.mcw.edu
A direct relationship exists between shear stress and endothelium-dependent NO-mediated vasodilation of blood vessels. The transduction of shear stress to the biochemical signals resulting in the production of NO is, however, unknown. We tested the hypothesis that integrin binding to Arg-Gly-Asp (RGD) peptide sequences in extracellular matrix proteins is a critical step in initiation of the signaling sequence whereby shear stress activates endothelial tyrosine kinase(s) and induces vasodilation of isolated arterioles. Isolated coronary arterioles were exposed to increasing shear stress under control conditions and in the presence of a synthetic peptide, GRGDNP, to competitively inhibit integrin binding to extracellular matrix proteins containing RGD peptide sequences. Intraluminal GRGDNP (0.1, 0.5, and 1.0 mmol/L) inhibited shear stress–induced vasodilation in a concentration-dependent manner. Application of GRGDNP had no effect on endothelium-dependent relaxation to substance P (10-12 to 10-8 mol/L). An inactive structural analogue, GRGESP, did not alter shear stress–induced vasodilation. To further elucidate the integrin involved in shear stress–induced vasodilation, we administered a blocking antibody to the integrin ß3 chain (F11) and observed significant attenuation of the vasodilation. Shear stress was also associated with an increase in tyrosine kinase activity, as assessed by anti-phosphotyrosine binding. Application of GRGDNP significantly decreased anti-phosphotyrosine binding during shear stress, suggesting a link between tyrosine kinase activation and integrin signaling during this vasodilatory response. Taken together, these results indicate that integrin-matrix interactions, possibly at focal adhesions, are of cardinal importance in the signaling pathway of shear stress–induced vasodilation.
Key Words: tyrosine kinase • endothelium • GRGDNP • nitric oxide • ß3 integrin