Role of Ca 2+ -Independent Phospholipase A 2 and Store-Operated Pathway in Urocortin-Induced Vasodilatation of Rat Coronary Artery

Abstract

Urocortin has been shown to produce vasodilatation in several arteries, but the precise mechanism of its action is still poorly understood. Here we demonstrate the role of store operated Ca²⁺ entry (SOCE) regulated by Ca²⁺-independent phospholipase A₂ (iPLA₂) in phenylephrine hydrochloride (PE)-induced vasoconstriction, and we present the first evidence that urocortin induces relaxation by the modulation of SOCE and iPLA₂ in rat coronary artery. Urocortin produces an endothelium independent relaxation, and its effect is concentration-dependent (IC₅₀≈4.5 nmol/L). We show in coronary smooth muscle cells (SMCs) that urocortin inhibits iPLA₂ activation, a crucial step for SOC channel activation, and prevents Ca²⁺ influx evoked by the emptying of the stores via a cAMP and protein kinase A (PKA)–dependent mechanism. Lysophophatidylcholine and lysophosphatidylinositol, products of iPLA₂, exactly mimic the effect of the depletion of the stores in presence of urocortin. Furthermore, we report that long treatment with urocortin downregulates iPLA₂ mRNA and proteins expression in rat coronary smooth muscle cells. In summary, we propose a new mechanism of vasodilatation by urocortin which involves the regulation of iPLA₂ and SOCE via the stimulation of a cAMP/PKA-dependent signal transduction cascade in rat coronary artery.