RGDN PEPTIDE INTERACTION WITH ENDOTHELIAL ALPHA(5)BETA(1) INTEGRIN CAUSES SUSTAINED ENDOTHELIN-DEPENDENT VASOCONSTRICTION OF RAT SKELETAL-MUSCLE ARTERIOLES

The ability of an integrin-binding Arg-Gly-Asp-Asn (RGDN)-containing p eptide to influence vascular tone by interacting with the alpha(5) bet a(1) integrin was studied using rat skeletal muscle arterioles. After blockade of beta(3) integrin function, isolated arterioles with sponta neous tone showed concentration-dependent vasoconstrictions to topical application of GRGDNP, a peptide that shows a greater ability to inte ract with alpha(5) beta(1) than with alpha(v) beta(3). The constrictio n to GRGDNP (2.1 mM) was inhibited by blocking alpha(5) integrin funct ion, and was intensified by blocking beta(3) integrin function. In con trast, GRGDSP, a peptide that interacts better with alpha(v) beta(3), was unable to induce sustained constrictions. Removal of the endotheli um abolished the vasoconstriction in response to GRGDNP, suggesting th at the response was due to release of an endothelium-dependent factor. Indeed, blockade of ETA endothelin receptors with BQ-610 (1 mu M), si milar to removal of the endothelium and alpha(5) integrin blockade, in hibited the vasoconstriction. These data indicate that interaction of RGD peptides, and in particular the RGDN sequence with endothelial cel l alpha(5) beta(1), causes endothelin-mediated arteriolar-vasoconstric tion. These results indicate that integrins are novel signaling recept ors within the vascular wall that affect vasomotor tone, and may play an important role in vascular control.