The pathological involvement of anion channels in vascular dysfunction that occurs during type 2 diabetes (T2D) is unclear. Here, we tested the hypothesis that TMEM16A, a calcium (Ca²⁺)-activated chloride (Cl^-) channel, contributes to modifications in arterial contractility during T2D. Our data indicate that T2D increased TMEM16A mRNA in arterial smooth muscle cells (myocytes) and total and surface TMEM16A protein in resistance-size arteries of mice. To examine vascular cell types in which TMEM16A expression is upregulated, we generated a tamoxifen-inducible, smooth muscle-specific TMEM16A knockout (TMEM16A smKO) mouse. T2D increased arterial TMEM16A protein and swelling-activated Cl^- currents in myocytes of control (TMEM16A^fl/fl) mice. In contrast, T2D did not alter arterial TMEM16A protein or Cl^- currents in myocytes of TMEM16A smKO mice. Arteries of T2D TMEM16A^fl/fl mice constricted more to intravascular pressure than those of non-diabetic TMEM16A^fl/fl mice. This elevated vasoconstriction produced in response to T2D was abolished in TMEM16A smKO mice. Akt2 protein was lower in arteries of T2D mice and siRNA-mediated knockdown of Akt2, but not Akt1, elevated TMEM16A protein in arteries of non-diabetic mice. Collectively, these data indicate that during T2D, a decrease in Akt2 expression stimulates TMEM16A expression in arterial myocytes, leading to vasoconstriction.

中文翻译：

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动脉平滑肌细胞中的 TMEM16A 通道上调在糖尿病期间产生血管收缩

阴离子通道在 2 型糖尿病 (T2D) 期间发生的血管功能障碍中的病理参与尚不清楚。在这里，我们检验了 TMEM16A 是一种钙 (Ca ²⁺ ) 激活的氯化物 (Cl ^- ) 通道在 T2D 期间有助于改变动脉收缩力的假设。我们的数据表明，T2D 增加了动脉平滑肌细胞（肌细胞）中的 TMEM16A mRNA 以及小鼠阻力大小动脉中的总和表面 TMEM16A 蛋白。为了检查 TMEM16A 表达上调的血管细胞类型，我们生成了他莫昔芬诱导的平滑肌特异性 TMEM16A 敲除 (TMEM16A smKO) 小鼠。T2D 增加了对照肌细胞中的动脉 TMEM16A 蛋白和肿胀激活的 Cl ^-电流 (TMEM16A ^fl/fl） 老鼠。相比之下，T2D 并未改变TMEM16A smKO 小鼠心肌细胞中的动脉 TMEM16A 蛋白或 Cl ^-电流。与非糖尿病 TMEM16A ^fl/fl小鼠相比，T2D TMEM16A ^fl/fl小鼠的动脉对血管内压力的收缩更多。在 TMEM16A smKO 小鼠中消除了对 T2D 产生的这种升高的血管收缩。Akt2 蛋白在 T2D 小鼠的动脉中较低，而 siRNA 介导的 Akt2 敲低，而不是 Akt1，则升高了非糖尿病小鼠动脉中的 TMEM16A 蛋白。总的来说，这些数据表明，在 T2D 期间，Akt2 表达的降低会刺激动脉肌细胞中 TMEM16A 的表达，从而导致血管收缩。