Increased TRPM4 Activity in Cerebral Artery Myocytes Contributes to Cerebral Blood Flow Reduction After Subarachnoid Hemorrhage in Rats
Increased TRPM4 Activity in Cerebral Artery Myocytes Contributes to Cerebral Blood Flow Reduction After Subarachnoid Hemorrhage in Rats
复制标题
脑动脉肌细胞中 TRPM4 活性增加导致大鼠蛛网膜下腔出血后脑血流量减少
DOI：
10.1007/s13311-019-00741-4
复制
发表时间：
2019-07-01
影响因子：
5.7
通讯作者：
Wang, Fei
中科院分区：
文献类型：
--
作者：
Gong, Yi;Du, Ming-yue;Wang, Fei
脑血流量（CBF）减少是蛛网膜下腔出血（SAH）后不良结局的基础。瞬时受体电位melastatin-4（TRPM-4）在生理条件下维持脑动脉肌源性张力和调节CBF中起关键作用。然而，TRPM 4在SAH后CBF减少中的作用尚不清楚。在这项研究中，我们的目的是测试TRPM 4是否有助于体内SAH后CBF减少，并确定潜在的机制。采用立体定向法于鞍上池注射自体非肝素化动脉血建立大鼠SAH模型。通过连接到程控皮下泵的脑室内导管输注TRPM 4阻滞剂9-菲咯（9-Phe），以评价TRPM 4对SAH结局的贡献。免疫印迹法检测脑动脉心肌细胞TRPM 4的表达和转位。采用全细胞膜片钳技术测定脑动脉肌细胞的宏观电流。用加压肌电描记术研究脑动脉肌源性张力。分别通过激光多普勒血流仪和荧光微球测量皮质和整体CBF。SAH后TRPM 4易位和宏观电流密度显著增加。此外，TRPM 4占SAH后肌源性张力的更大比例，表明TRPM 4活性响应SAH而上调。SAH后皮质和整体CBF减少，但9-Phe显著恢复，这意味着TRPM 4有助于SAH后CBF减少。总的来说，这些发现表明TRPM 4活性增加在SAH后CBF减少中具有关键作用，并为SAH后脑灌注功能障碍的管理提供了新的靶点。
Cerebral blood flow (CBF) reduction underlies unfavorable outcomes after subarachnoid hemorrhage (SAH). Transient receptor potential melastatin-4 (TRPM4) has a pivotal role in cerebral artery myogenic tone maintenance and CBF regulation under physiological conditions. However, the role of TRPM4 in CBF reduction after SAH is unclear. In this study, we aimed at testing whether TRPM4 would contribute to CBF reduction after SAH in vivo and determining underlying mechanisms. Rat SAH model was established by stereotaxic injection of autologous nonheparinized arterial blood at the suprasellar cistern. A TRPM4 blocker, 9-phenanthrol (9-Phe), was infused through an intraventricular catheter connected to a programmed subcutaneous pump to evaluate the contribution of TRPM4 to SAH outcomes. TRPM4 expression and translocation in cerebral artery myocytes were detected by immunoblotting. Macroscopic currents in cerebral artery myocytes were determined by whole-cell patch clamp. Myogenic tone of cerebral arteries was studied by pressurized myography. Cortical and global CBFs were measured via laser Doppler flowmetry and fluorescent microspheres, respectively. After SAH, TRPM4 translocation and macroscopic current density increased significantly. Furthermore, TRPM4 accounted for a greater proportion of myogenic tone after SAH, suggesting an upregulation of TRPM4 activity in response to SAH. Cortical and global CBFs were reduced after SAH, but were restored significantly by 9-Phe, implying that TRPM4 contributed to CBF reduction after SAH. Collectively, these discoveries show that increased TRPM4 activity has a pivotal role in CBF reduction after SAH, and provide a novel target for the management of cerebral perfusion dysfunction following SAH.