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：

---

动脉平滑肌细胞中 TMEM16A 通道的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。在此，我们测试了以下假设：TMEM16A（一种钙 (Ca ²⁺ ) 激活的氯 (Cl ^- ) 通道）有助于 T2D 期间动脉收缩力的改变。我们的数据表明，T2D 增加了小鼠动脉平滑肌细胞（肌细胞）中的 TMEM16A mRNA 以及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 增加了对照组 (TMEM16A ^fl/fl ) 小鼠的动脉 TMEM16A 蛋白和肿胀激活的 Cl ^-电流。相比之下，T2D 不会改变 TMEM16A smKO 小鼠的动脉 TMEM16A 蛋白或肌细胞中的 Cl ^-电流。 T2D TMEM16A ^fl/fl小鼠的动脉比非糖尿病 TMEM16A ^fl/fl小鼠的动脉因血管内压力而收缩更多。这种因 T2D 反应而产生的血管收缩升高在 TMEM16A smKO 小鼠中被消除。 T2D 小鼠动脉中的 Akt2 蛋白较低，siRNA 介导的 Akt2 敲低（而非 Akt1），非糖尿病小鼠动脉中的 TMEM16A 蛋白升高。总的来说，这些数据表明，在 T2D 期间，Akt2 表达的减少会刺激动脉肌细胞中 TMEM16A 的表达，从而导致血管收缩。