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- W2892033722 abstract "Abstract Basal forebrain neurons control cerebral blood flow (CBF) by releasing acetylcholine (Ach), which binds to endothelial muscarinic receptors to induce nitric (NO) release and vasodilation in intraparenchymal arterioles. Nevertheless, the mechanism whereby Ach stimulates human brain microvascular endothelial cells to produce NO is still unknown. Herein, we sought to assess whether Ach stimulates NO production in a Ca 2+ ‐dependent manner in hCMEC/D3 cells, a widespread model of human brain microvascular endothelial cells. Ach induced a dose‐dependent increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) that was prevented by the genetic blockade of M5 muscarinic receptors (M5‐mAchRs), which was the only mAchR isoform coupled to phospholipase Cβ (PLCβ) present in hCMEC/D3 cells. A comprehensive real‐time polymerase chain reaction analysis revealed the expression of the transcripts encoding for type 3 inositol‐1,4,5‐trisphosphate receptors (InsP 3 R3), two‐pore channels 1 and 2 (TPC1–2), Stim2, Orai1–3. Pharmacological manipulation showed that the Ca 2+ response to Ach was mediated by InsP 3 R3, TPC1–2, and store‐operated Ca 2+ entry (SOCE). Ach‐induced NO release, in turn, was inhibited in cells deficient of M5‐mAchRs. Likewise, Ach failed to increase NO levels in the presence of l ‐NAME, a selective NOS inhibitor, or BAPTA, a membrane‐permeant intracellular Ca 2+ buffer. Moreover, the pharmacological blockade of the Ca 2+ response to Ach also inhibited the accompanying NO production. These data demonstrate for the first time that synaptically released Ach may trigger NO release in human brain microvascular endothelial cells by stimulating a Ca 2+ signal via M5‐mAchRs." @default.
- W2892033722 created "2018-09-27" @default.
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- W2892033722 date "2018-09-07" @default.
- W2892033722 modified "2023-09-26" @default.
- W2892033722 title "Muscarinic M5 receptors trigger acetylcholine‐induced Ca<sup>2+</sup> signals and nitric oxide release in human brain microvascular endothelial cells" @default.
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