Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee.
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee.
Am J Physiol Heart Circ Physiol. 2021 Mar 1;320(3):H1089-H1101. doi: 10.1152/ajpheart.00690.2020. Epub 2021 Jan 15.
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-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 and total and surface TMEM16A protein in resistance-size cerebral and hindlimb arteries of mice. To examine vascular cell types in which TMEM16A protein increased and the functional consequences of TMEM16A upregulation during T2D, we generated tamoxifen-inducible, smooth muscle cell-specific TMEM16A knockout ( smKO) mice. T2D increased both TMEM16A protein and Cl current density in arterial smooth muscle cells of control () mice. In contrast, T2D did not alter arterial TMEM16A protein or Cl current density in smooth muscle cells of smKO mice. Intravascular pressure stimulated greater vasoconstriction (myogenic tone) in the arteries of T2D mice than in the arteries of nondiabetic mice. This elevation in myogenic tone in response to T2D was abolished in the arteries of T2D smKO mice. T2D also reduced Akt2 protein and activity in the arteries of T2D mice. siRNA-mediated knockdown of Akt2, but not Akt1, increased arterial TMEM16A protein in nondiabetic mice. In summary, data indicate that T2D is associated with an increase in TMEM16A expression and currents in arterial smooth muscle cells that produces vasoconstriction. Data also suggest that a reduction in Akt2 function drives these pathological alterations during T2D. We investigated the involvement of TMEM16A channels in vascular dysfunction during type 2 diabetes (T2D). TMEM16A message, protein, and currents were higher in smooth muscle cells of resistance-size arteries during T2D. Pressure stimulated greater vasoconstriction in the arteries of T2D mice that was abolished in the arteries of smKO mice. Akt2 protein and activity were both lower in T2D arteries, and Akt2 knockdown elevated TMEM16A protein. We propose that a decrease in Akt2 function stimulates TMEM16A expression in arterial smooth muscle cells, leading to vasoconstriction during T2D.
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作用尚不清楚。在这里，我们检验了一个假设，即钙激活氯离子（Cl）通道 TMEM16A 有助于 T2D 期间动脉收缩性的改变。我们的数据表明，T2D 增加了动脉平滑肌细胞中的 TMEM16A mRNA 以及阻力大小的脑和后肢动脉中的总 TMEM16A 和表面 TMEM16A 蛋白。为了研究 TMEM16A 蛋白增加的血管细胞类型以及 T2D 期间 TMEM16A 上调的功能后果，我们生成了可诱导的、平滑肌细胞特异性 TMEM16A 敲除（smKO）小鼠。T2D 增加了对照组（）小鼠动脉平滑肌细胞中的 TMEM16A 蛋白和 Cl 电流密度。相比之下，T2D 没有改变 smKO 小鼠动脉平滑肌细胞中的动脉 TMEM16A 蛋白或 Cl 电流密度。血管内压力刺激 T2D 小鼠的血管收缩（肌源性张力）大于非糖尿病（nondiabetic）小鼠的血管收缩。T2D 小鼠对 T2D 的肌源性张力升高在 T2D 小鼠的 smKO 动脉中被消除。T2D 还降低了 T2D 小鼠动脉中的 Akt2 蛋白和活性。siRNA 介导的 Akt2 敲低，但不是 Akt1，增加了非糖尿病小鼠的动脉 TMEM16A 蛋白。总之，数据表明，T2D 与动脉平滑肌细胞中 TMEM16A 表达和电流的增加有关，从而导致血管收缩。数据还表明，Akt2 功能的降低在 T2D 期间驱动了这些病理改变。我们研究了 TMEM16A 通道在 2 型糖尿病（T2D）期间血管功能障碍中的作用。T2D 期间，阻力大小的动脉平滑肌细胞中的 TMEM16A 信息、蛋白和电流更高。压力刺激 T2D 小鼠的血管收缩更大，在 smKO 小鼠的动脉中被消除。Akt2 蛋白和活性在 T2D 动脉中均降低，而 Akt2 敲低则升高了 TMEM16A 蛋白。我们提出，Akt2 功能的降低刺激了动脉平滑肌细胞中 TMEM16A 的表达，导致 T2D 期间血管收缩。
