Integrin Ligands Mobilize Ca2+ from Ryanodine Receptor-gated Stores and Lysosome-related Acidic Organelles in Pulmonary Arterial Smooth Muscle Cells.
Extracellular matrix ( ECM) protein receptors, or integrins, participate in vascular remodeling and the systemic myogenic response. Synthetic ligands and ECM fragments regulate the vascular smooth muscle cell contractile state by altering intracellular Ca(2+) levels ([Ca(2+)](i)). Information on the Ca(2+) effect of integrins in vascular smooth muscle cells is limited, but nonexistent in pulmonary arterial smooth muscle cells (PASMCs). We therefore characterized integrin expression in endothelium-denuded pulmonary arteries, and explored [Ca(2+)](i) mobilization pathways induced by soluble ligands in rat PASMCs. Reverse transcriptase-PCR showed mRNA expression of integrins alpha(1), alpha(2), alpha(3), alpha(4), alpha(5), alpha(7), alpha(8), alpha(v), beta(1), beta(3), and beta(4), and immunoblots of alpha(5), alpha(v), beta(1), and beta(3) confirmed protein expression. Exposure of PASMCs to integrin-binding peptides (0.5 mm) containing the arginine-glycine-aspartate (RGD) motif elicited [Ca(2+)](i) responses with an order of potency of GRGDNP > GRGDSP > GRGDTP = cyclo-RGD. Pharmacological analysis revealed that the GRGDSP-induced Ca(2+) response was unrelated to Ca(2+) influx and the inositol triphosphate receptor-gated Ca(2+) store, but partially blocked by ryanodine or inhibition of lysosomerelated acidic organelles with bafilomycin A1. Simultaneous inhibition of both pathways was necessary to abolish the response. GRGDSP treatment increased cyclic ADP-ribose, the endogenous activator of ryanodine receptors, by 70%. GRGDSP also rapidly reduced Lysotracker Red accumulation, confirming direct modulation of acidic organelles. These data are the first demonstration of integrin-mediated Ca(2+) regulation in PASMCs. The presence of an array of integrins, and activation of ryanodine-sensitive Ca(2+) stores and lysosome-like organelles by GRGDSP suggest important roles for integrin-dependent Ca(2+) signaling in regulating PASMC function.[1]References
- Integrin Ligands Mobilize Ca2+ from Ryanodine Receptor-gated Stores and Lysosome-related Acidic Organelles in Pulmonary Arterial Smooth Muscle Cells. Umesh, A., Thompson, M.A., Chini, E.N., Yip, K.P., Sham, J.S. J. Biol. Chem. (2006) [Pubmed]
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