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Role of iPLA₂ and store-operated channels in agonist-induced Ca²⁺ influx and constriction in cerebral, mesenteric, and carotid arteries

¹Ion Channel and Calcium Signaling Unit and ²Vascular Biology Unit, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts

Submitted 3 October 2007 ; accepted in final form 19 December 2007

Store-operated channels (SOC) and store-operated Ca²⁺ entry are known to play a major role in agonist-induced constriction of smooth muscle cells (SMC) in conduit vessels. In microvessels the role of SOC remains uncertain, in as much as voltage-gated L-type Ca²⁺ (Ca_L²⁺) channels are thought to be fully responsible for agonist-induced Ca²⁺ influx and vasoconstriction. We present evidence that SOC and their activation via a Ca²⁺-independent phospholipase A₂ (iPLA₂)-mediated pathway play a crucial role in agonist-induced constriction of cerebral, mesenteric, and carotid arteries. Intracellular Ca²⁺ in SMC and intraluminal diameter were measured simultaneously in intact pressurized vessels in vitro. We demonstrated that 1) Ca²⁺ and contractile responses to phenylephrine (PE) in cerebral and carotid arteries were equally abolished by nimodipine (a Ca_L²⁺ inhibitor) and 2-aminoethyl diphenylborinate (an inhibitor of SOC), suggesting that SOC and Ca_L²⁺ channels may be involved in agonist-induced constriction of cerebral arteries, and 2) functional inhibition of iPLA₂β totally inhibited PE-induced Ca²⁺ influx and constriction in cerebral, mesenteric, and carotid arteries, whereas K⁺-induced Ca²⁺ influx and vasoconstriction mediated by Ca_L²⁺ channels were not affected. Thus iPLA₂-dependent activation of SOC is crucial for agonist-induced Ca²⁺ influx and vasoconstriction in cerebral, mesenteric, and carotid arteries. We propose that, on PE-induced depletion of Ca²⁺ stores, nonselective SOC are activated via an iPLA₂-dependent pathway and may produce a depolarization of SMC, which could trigger a secondary activation of Ca_L²⁺ channels and lead to Ca²⁺ entry and vasoconstriction.

store-operated calcium entry; smooth muscle cells; constriction

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