Amount of Pannexin 1 in Smooth Muscle Cells Regulates Sympathetic Nerve-Induced Vasoconstriction.
Amount of Pannexin 1 in Smooth Muscle Cells Regulates Sympathetic Nerve-Induced Vasoconstriction.
复制标题
平滑肌细胞中 Pannexin 1 的量调节交感神经诱导的血管收缩。
DOI：
10.1161/hypertensionaha.122.20280
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Isakson,BrantE
中科院分区：
文献类型：
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作者：
Dunaway,LukeS;Billaud,Marie;Macal,Edgar;Good,MirandaE;Medina,ChristopherB;Lorenz,Ulrike;Ravichandran,Kodi;Koval,Michael;Isakson,BrantE
背景：Panx1(PAnnexin 1)形成高电导通道，在刺激下分泌ATP。Panx1在直接交感神经刺激引起的收缩反应中的作用尚不清楚。此外，尚不清楚PANX1在平滑肌细胞(SMC)中的表达水平如何影响α-肾上腺素能反应。我们假设SMC中Panx1的数量决定了交感神经收缩和血压的水平。方法为了验证这一假设，我们使用了能够改变Panx1在血管细胞中表达的转基因小鼠模型。结果SMC Panx1基因缺失可抑制电场刺激交感神经引起的收缩。相反，使用rosa26转基因模型在SMC中过表达Panx1会增加交感神经介导的收缩。缝隙连接蛋白43半通道抑制剂不能改变收缩。接下来，我们评估了SMC Panx1表达变化对血压的影响。为了做到这一点，我们创造了结合全局Panx1缺失的小鼠，在可诱导的SMC特异性Cre(MYH11)的控制下与rosa26-Panx1结合。这导致小鼠只能在SMC中表达人Panx1。服用他莫昔芬后，这些小鼠的血压升高，而Panx1抑制剂螺内酯显著降低了血压。基因缺失Panx1的对照组小鼠对螺内酯无反应。结论SMC中Panx1对交感神经收缩程度和血压有调节作用。结果还表明人源化的Panx1-小鼠模型用于药理候选测试的可行性。
BackgroundPanx1 (pannexin 1) forms high conductance channels that secrete ATP upon stimulation. The role of Panx1 in mediating constriction in response to direct sympathetic nerve stimulation is not known. Additionally, it is unknown how the expression level of Panx1 in smooth muscle cells (SMCs) influences α-adrenergic responses. We hypothesized that the amount of Panx1 in SMCs dictates the levels of sympathetic constriction and blood pressure.MethodsTo test this hypothesis, we used genetically modified mouse models enabling expression of Panx1 in vascular cells to be varied. Electrical field stimulation on isolated arteries and blood pressure were assessed.ResultsGenetic deletion of SMC Panx1 prevented constriction by electric field stimulation of sympathetic nerves. Conversely, overexpression of Panx1 in SMCs using a ROSA26 transgenic model increased sympathetic nerve-mediated constriction. Connexin 43 hemichannel inhibitors did not alter constriction. Next, we evaluated the effects of altered SMC Panx1 expression on blood pressure. To do this, we created mice combining a global Panx1 deletion, with ROSA26-Panx1 under the control of an inducible SMC specific Cre (Myh11). This resulted in mice that could express only human Panx1, only in SMCs. After tamoxifen, these mice had increased blood pressure that was acutely decreased by the Panx1 inhibitor spironolactone. Control mice genetically devoid of Panx1 did not respond to spironolactone.ConclusionsThese data suggest Panx1 in SMCs could regulate the extent of sympathetic nerve constriction and blood pressure. The results also show the feasibility humanized Panx1-mouse models to test pharmacological candidates.