Vascular Smooth Muscle α _v β ₃ Integrin Mediates Arteriolar Vasodilation in Response to RGD Peptides

Abstract

Arteriolar vasodilation and the resultant increase in blood flow are characteristic vascular responses to tissue injury. The dilatory mediators signaling these responses are incompletely understood. We show that integrin-binding peptides containing the Arg-Gly-Asp (RGD) tripeptide sequence cause immediate and, in some instances, sustained vasodilation when applied to isolated rat cremaster arterioles. The vasodilation is dependent on interaction of the soluble RGD sequence with the alpha v beta 3 integrin expressed by smooth muscle cells in the arteriolar wall. Possible in vivo sources of soluble RGD sequences are fragments of extracellular matrix proteins that are generated after tissue injury. Indeed, protease-generated fragments of denatured collagen type I (a major source of RGD sequences) also cause cremaster arteriolar vasodilation through the alpha v beta 3 integrin. Thus, extracellular matrix protein fragments containing the RGD sequence may act as vascular wound recognition signals to regulate blood flow to injured tissue.

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

“…Although many studies indicate that synthetic RGD-containing peptides inhibit angiogenesis and tumor growth, our findings provide the first evidence that macrophages may generate and release an RGDKGE-containing collagen epitope that may exhibit pro-angiogenic activity. Importantly, previous studies have suggested that certain RGD peptides can activate ␣v␤3 (58,59) and may enhance vascular permeability (45,57), which might lead to release of inflammatory factors, which in turn may contribute to the formation of new blood vessels.…”

RGDN peptide interaction with endothelial alpha5beta1 integrin causes sustained endothelin-dependent vasoconstriction of rat skeletal muscle arterioles.

“…The preparation of isolated arterioles for study has been previously described in detail (20). In brief, male SpragueDawley rats (180-300 g) were anesthetized with pentobarbital sodium (100 mg/kg i.p.).…”

“…In the isolated arteriole preparation, GRGDNP, GRGDSP, and a cyclic RGD peptide (GPenGRGDSPCA where Pen ϭ penicillamine; Gibco BRL) induce concentration-dependent arteriolar dilation with the cyclic peptide showing greater potency consistent with its predominant ␣ v ␤ 3 -binding properties (20). The purpose of these experiments was to determine if the role of ␣ 5 ␤ 1 would be made evident after blockade of ␤ 3 integrin function.…”

“…We recently demonstrated that soluble synthetic RGD peptides cause vasodilation of isolated rat skeletal muscle arterioles by interacting with the vascular smooth muscle (VSMC) integrin ␣ v ␤ 3 (20). On the basis of these studies, we proposed that other VSMC or endothelial cell (EC) integrins capable of interacting with RGD could also be involved in vascular control.…”

The Role of Actin Filament Dynamics in the Myogenic Response of Cerebral Resistance Arteries

“…Evidence has been provided in support of a role for integrins in the myogenic response, 22 which was found to be suppressed by integrin-specific peptides and blocking antibodies. 20,21,23 Smooth muscle integrins are located in membrane-associated dense plaques, structural analogs of focal adhesions of cultured cells. 24 Integrin stimulation (clustering) induces tyrosine phosphorylation and activation of focal adhesion kinase (FAK) and Src family tyrosine kinases, and increased tyrosine phosphorylation is associated with the myogenic response.…”