Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Basic Clin Pharmacol Toxicol. 2018 Jul;123(1):30-41. doi: 10.1111/bcpt.12984. Epub 2018 Mar 30.
TMEM16A is essential for Ca -activated Cl conductance in vascular smooth muscle. The importance of TMEM16A for agonist-induced vascular constriction and blood pressure control is, however, under debate. Previous studies suggested that TMEM16A might have a complex cellular function beyond being essential for the Ca -activated Cl conductance, for example modulation of Ca channel expression. Mice with constitutive, smooth muscle-specific expression of siRNA directed against Tmem16a (transgenic mice, TG) were generated. Isometric constrictions of isolated aorta, mesenteric, femoral and tail arteries from TG mice were compared with wild-types. Protein expression was analysed by Western blots. Blood pressure and heart rate were studied telemetrically. Significant TMEM16A down-regulation was seen in aorta and tail arteries, while no changes were detected in mesenteric and femoral arteries. Contractile responses of mesenteric and femoral arteries from TG and wild-type mice were not different. Aorta from TG mice showed reduced agonist-induced constriction, while their responses to elevated K were unchanged. Tail arteries from TG mice also constricted less to adrenergic stimulation than wild-types. Surprisingly, tail arteries from TG mice constricted less to elevated K too and were more sensitive to nifedipine-induced relaxation. Consistently, TMEM16A down-regulation in tail arteries was associated with reduction in CACNA1C protein (i.e. vascular L-type Ca channel) expression. No differences in blood pressure and heart rate between the groups were seen. This study suggests a complex contribution of TMEM16A in vascular function. We suggest that TMEM16A modulates arterial contractility, at least in part, indirectly via regulation of CACNA1C expression.
TMEM16A 对于血管平滑肌中的 Ca2+激活的 Cl-电导至关重要。然而，TMEM16A 对于激动剂诱导的血管收缩和血压控制的重要性仍存在争议。先前的研究表明，TMEM16A 的功能可能比 Ca2+激活的 Cl-电导更为复杂，例如调节 Ca 通道的表达。我们构建了平滑肌特异性过表达 siRNA 靶向 Tmem16a 的基因敲入（TG）小鼠。通过比较 TG 小鼠和野生型小鼠的离体主动脉、肠系膜、股动脉和尾动脉的等长收缩来研究其血管功能。通过 Western blot 分析蛋白表达，通过遥测法研究血压和心率。在主动脉和尾动脉中观察到 TMEM16A 的显著下调，而在肠系膜和股动脉中则未检测到变化。TG 和野生型小鼠的肠系膜和股动脉的收缩反应没有差异。TG 小鼠的主动脉对激动剂诱导的收缩反应减弱，而对升高的 K 的反应不变。与野生型相比，TG 小鼠的尾动脉对肾上腺素刺激的收缩反应也较弱。令人惊讶的是，TG 小鼠的尾动脉对升高的 K 的收缩反应也较弱，并且对硝苯地平诱导的舒张更为敏感。一致地，尾动脉中 TMEM16A 的下调与 CACNA1C 蛋白（即血管 L 型 Ca 通道）表达的减少有关。两组间的血压和心率没有差异。本研究表明 TMEM16A 在血管功能中具有复杂的作用。我们认为 TMEM16A 通过调节 CACNA1C 的表达，间接地调节动脉的收缩性。
