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 peptide to influence vascular tone by interacting with the alpha(5) beta(1) integrin was studied using rat skeletal muscle arterioles. After blockade of beta(3) integrin function, isolated arterioles with spontaneous tone showed concentration-dependent vasoconstrictions to topical application of GRGDNP, a peptide that shows a greater ability to interact with alpha(5) beta(1) than with alpha(v) beta(3). The constriction to GRGDNP (2.1 mM) was inhibited by blocking alpha(5) integrin function, and was intensified by blocking beta(3) integrin function. In contrast, GRGDSP, a peptide that interacts better with alpha(v) beta(3), was unable to induce sustained constrictions. Removal of the endothelium abolished the vasoconstriction in response to GRGDNP, suggesting that the response was due to release of an endothelium-dependent factor. Indeed, blockade of ETA endothelin receptors with BQ-610 (1 mu M), similar to removal of the endothelium and alpha(5) integrin blockade, inhibited the vasoconstriction. These data indicate that interaction of RGD peptides, and in particular the RGDN sequence with endothelial cell alpha(5) beta(1), causes endothelin-mediated arteriolar-vasoconstriction. These results indicate that integrins are novel signaling receptors within the vascular wall that affect vasomotor tone, and may play an important role in vascular control.