Modulation of Calcium Current in Arteriolar Smooth Muscle by αvβ3 and α5β1 Integrin Ligands

Abstract

Vasoactive effects of soluble matrix proteins and integrin-binding peptides on arterioles are mediated by αvβ3 and α5β1 integrins. To examine the underlying mechanisms, we measured L-type Ca2+ channel current in arteriolar smooth muscle cells in response to integrin ligands. Whole-cell, inward Ba2+ currents were inhibited after application of soluble cyclic RGD peptide, vitronectin (VN), fibronectin (FN), either of two anti–β3 integrin antibodies, or monovalent β3 antibody. With VN or β3 antibody coated onto microbeads and presented as an insoluble ligand, current was also inhibited. In contrast, beads coated with FN or α5 antibody produced significant enhancement of current after bead attachment. Soluble α5 antibody had no effect on current but blocked the increase in current evoked by FN-coated beads and enhanced current when applied in combination with an appropriate IgG. The data suggest that αvβ3 and α5β1 integrins are differentially linked through intracellular signaling pathways to the L-type Ca2+ channel and thereby alter control of Ca2+ influx in vascular smooth muscle. This would account for the vasoactive effects of integrin ligands on arterioles and provide a potential mechanism for wound recognition during tissue injury.

Integrin regulation of cytoplasmic calcium in excitatory neurons depends upon glutamate receptors and release from intracellular stores

“…First, AMPAR-mediated synaptic events may be permissive and simply provide the intermittent depolarization needed to allow integrin signaling influences on the otherwise voltage-blocked NMDARs and VSCCs to become manifest. Studies of nonneural cells have shown that integrins signal through FAK and Src kinases to phosphorylate and increase activities of plasma membrane calcium channels (Wu et al, 1998;Wu et al, 2001;Gui et al, 2006); we have shown similar integrin signaling effects on the NMDARs (Bernard-Trifilo et al, 2005). Second, direct integrin modulation of AMPA receptor function may be an important upstream event.…”

“…Moreover, when examined, influx is generally found to be mediated by VSCCs and dependent upon tyrosine kinase signaling (i.e., blocked by genistein) (Wu et al, 1998;Kwon et al, 2000;Wu et al, 2001). What distinguishes effects in neurons is the participation of neuron-specific receptors that produce depolarization (AMPA receptors) and voltage-dependent influx (e.g., NMDA receptors).…”

The Plastic Nature of the Vascular Wall: A Continuum of Remodeling Events Contributing to Control of Arteriolar Diameter and Structure

“…Integrins are the best characterized of the adhesion receptors for extracellular matrix components providing cells with the ability to adhere to surrounding connective tissue (FIGURE 3 (109,116,117,177,178). It has also been observed that the expression of these two integrins is increased in mesenteric arteries from spontaneously hypertensive rats (88), possibly accounting for the increased vascular myogenic tone reported in these animals (58, 59, 149).…”

Blast-induced phenotypic switching in cerebral vasospasm

“…Integrins are the primary transducers of mechanical force to the cell's cytoskeleton (36,37), and integrin stimulation is involved in a wide range of cellular signaling, including altering calcium dynamics (11,12) and phenotypic behavior (38)(39)(40) in VSMCs. The mechanical loading of the blast and the resulting hypercontractility both likely result in abnormal integrin stimulation, potentially mediating the observed vasospasm behavior.…”

“…In vitro studies of vascular smooth muscle have revealed that direct stimulation of integrins induces enhanced calcium activity (11,12) and myosin light chain phosphorylation (13). Cyclic mechanical stimulation within physiological ranges induces populations of vascular smooth muscle cells (VSMCs) to shift toward a contractile phenotype (14), while mechanical stresses of a higher magnitude, mimicking chronic hypertension, induce smooth muscle proliferation and extracellular matrix (ECM) remodeling (15).…”