TRPM7通道介导Ca2+/ADAM17/EGFR信号通路在脑血管重构中的作用研究

In vascular remodeling, media growth of a blood vessel results in a decreased lumen and may involve increased SMC number, size, or both. Our primary data showed that TRPM7 protein expression was increased during hypertension induced vascular remodeling. Inhibition of TRPM7 has indicated the significant reduction in media to lumen ratio. TRPM7 can regulate intracellular Ca2+ level. Both knockdown and inhibition of TRPM7 reduced the activity of ADAM17. Our present study aimed to further clarify how TRPM7 interferes with the activity of ADAM17/EGFR signaling pathway and thus regulates cellular proliferation and hypertrophy. Moreover, we will investigate the functional role of TRPM7 in regulating hypertension induced cerebral vascular remodeling. This work will reveal the new functions of TRPM7 and raise the possibility that TRPM7 is a key regulator of Ca2+/ADAM17/EGFR pathway, suggesting that TRPM7 may be a novel therapeutic target for hypertension induced cerebral vascular remodeling.

血管重构与平滑肌细胞内钙浓度升高及其信号转导紊乱密切相关，但机制未明。预实验显示，TRPM7蛋白表达在高血压脑血管重构中明显升高。给予TRPM7特异性抑制剂8周明显改善脑血管重构。结果提示TRPM7介导的Ca2+信号发挥重要作用。进一步发现，平滑肌细胞上，TRPM7通道开放激活金属蛋白酶ADAM17。ADAM17是EGFR转录活化的关键，后者促进血管重构，因此我们假设，TRPM7/Ca2+/ADAM17/EGFR是高血压脑血管重构的重要信号通路。本项目拟在上述工作基础上：①探讨TRPM7在Ang II引起钙浓度升高及平滑肌细胞增殖和肥大中的作用，并研究其机制；②进一步在体检测TRPM7敲除或通道抑制，对高血压脑血管重构的影响。本研究提出TRPM7可能是调控Ca2+/ADAM17/EGFR信号通路关键分子，并为评估TRPM7可否作为防治高血压脑血管重构新靶点提供实验依据。

血管重构与平滑肌细胞内钙浓度升高及其信号转导紊乱密切相关，但机制未明。实验显示，TRPM7蛋白表达在高血压脑血管重构中明显升高。给予TRPM7特异性抑制剂8周明显改善脑血管重构。结果提示TRPM7介导的Ca2+信号发挥重要作用。进一步发现，平滑肌细胞上，TRPM7通道开放激活金属蛋白酶ADAM17。ADAM17是EGFR转录活化的关键，后者促进血管重构，因此我们假设，TRPM7/Ca2+/ADAM17/EGFR是高血压脑血管重构的重要信号通路。实验发现：血管紧张素Ⅱ可以浓度依赖性诱导TRPM7通道蛋白表达，同时激活TRPM7通道电流。沉默TRPM7通道的表达，可以抑制血管紧张素Ⅱ诱导的平滑肌细胞计数的升高、BrdU 阳性细胞比例明显升高、细胞周期的转换。抑制TRPM7通道活性，可以抑制血管紧张素Ⅱ诱导的平滑肌细胞计数的升高、BrdU 阳性细胞比例明显升高、Ki67蛋白的表达。抑制TRPM7通道能明显逆转高血压并发的血管肥厚重构。本研究提出TRPM7可能调控Ca2+/ADAM17/EGFR信号通路参与脑血管重构，并为评估TRPM7可否作为防治高血压脑血管重构新靶点提供实验依据。