Crosstalk Signaling Between cAMP and Calcium on the Leading Edge of Migrating Human Arterial Vascular Smooth Muscle Cells
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Vascular smooth muscle cells (VSMCs) are phenotypically plastic. Thus, while the VSMCs in healthy blood vessels are ‘contractile’ and control vascular tone, these cells can increase their synthetic, migratory and proliferative capacities in response to vessel injury. While largely adaptive, actions of “synthetic” VSMCs can promote arterial wall thickening and contribute to atherosclerosis and vessel stenosis. Currently, vessel stenosis is reversed by percutaneous coronary intervention (PCI) and the placement of drug eluting stents (DES) coated with pan-cellular anti-proliferative agents. Although these approaches are effective, in-stent restenosis and thrombosis remain problematic, in part due to limited re-endothelialization. Thus, DESs coated with drugs targeting specifically synthetic VSMCs, but not the endothelium, might limit these problems. Since the cyclic nucleotide phosphodiesterase, PDE1C, a dual cAMP/cGMP hydrolyzing PDE, is exclusively expressed by synthetic VSMCs and regulates their synthetic, migratory and proliferative actions, it may represent a valid synthetic VSMC specific therapeutic target. Store operated calcium entry (SOCE) allows refilling of depleted ER-Ca2+ stores in non-excited cells, including in synthetic VSMCs, and supports migration and proliferation of synthetic VSMCs. Herein, we identify a critical role for PDE1C in regulating the polarization of synthetic human arterial VSMCs (HASMCs) required for their migration and show how this PDE acts as a nexus allowing reciprocal regulation of the SOCE- and cAMP-signaling systems in these cells. Thus, we show that PDE1C localizes at lamellipodia formed by polarized/migrating HASMCs and coordinates a series of hyper-localized Ca2+ and cAMP signaling events within these structures which chronically antagonize their formation. Moreover, we show that these events are dependent on localized actions of the SOCE promoting machinery (i.e. Orai1/STIM1), a Ca2+-activated adenylyl cyclase (ADCY8), PKA and the A-kinase anchoring protein (AKAP79). Based on our findings, we suggest that inhibiting the actions of PDE1C may represent a valid novel therapeutic approach to decrease the burden associated with unregulated migration and proliferation of synthetic VSMCs.