前期系列进展表明“离子失稳态”导致高血压脑血管重构，但TRP通道超家族的贡献知之甚少。筛查通道亚型，首次发现TRPM7在三种高血压模型均一致上调，waixA药物在体阻断显著抑制双肾双夹大鼠脑血管重构。TRPM7结构独特，兼具离子通道与激酶功能；预实验：①基因敲除后功能重建，首次发现通道促血管平滑肌增殖，而激酶促氧化应激，二者差异性调控血管重构关键步骤；②通道招募CaMKIIγ转导钙信号；③激酶表观抑制NRROS（氧化应激负向调控因子）转录。提出假设：通道开放后激活CaMKIIγ转运calmodulin入核，结合cyclinE而促细胞增殖；而激酶作为新型表观调控因子促氧化应激，磷酸化NRROS基因H3S28而促进EZH2三甲基化H3K27，NRROS沉默后增加NOX2蛋白稳定性。拟基因敲除与药物阻断并用，从“通道与激酶”新角度揭示高血压脑血管重构机制，确证TRPM7是高血压脑卒中防治新靶标。

We have previously demonstrated, in a series of studies, that ionic perturbation is a major contributor to hypertension-induced cerebrovascular remodeling, but the role of TRP (Transient Receptor Potential) channel superfamily remains largely unknown. By q-PCR screening of TRP channel subtypes, we, for the first time, found that TRPM7 was consistently upregulated in 3 distinct animal models of hypertension, and that in vivo inhibition of TRPM7 with waixenicin A, a newly identified TRPM7 blocker, significantly attenuated cerebrovascular remodeling in 2-kidney-2-clip hypertensive rats. TRPM7 is a unique bifunctional channel with its channel pore fused to a carboxyl-terminal α kinase, and it displays both channel and kinase activity. Rescue experiments in TRPM7 knockout cells with channel or kinase-encoding constructs revealed that channel activity was required for vascular smooth muscle cell proliferation and that kinase functionality was critical for oxidative stress; therefore, channel and kinase activity differentially regulated the 2 key processes in cerebrovascular remodeling. APEX-2 mediated proximity labeling revealed that TRPM7, upon opening, recruited CaMKIIγ to conduct Ca2+ signaling. The kinase epigenetically repressed the transcription of NRROS (Negative Regulator of ROS), a key negative modulator of oxidative stress that functions by binding to and promoting the degradation of NOX2 in the endoplasmic reticular membrane. Based upon our preliminary data, we hypothesized that the TRPM7 channel kinase contributes to cerebrovascular remodeling by means of channel-mediated Ca2+ influx and kinase-elicited epigenetic modification. Specifically, TRPM7 channel bound to and activated CaMKIIγ, which shuttles calmodulin to the nucleus to complex with cyclin E, triggering cell proliferation. The kinase, being a novel epigenetic modulator, phosphorylated H3S28 of NRROS, enhancing EZH2-mediated methylation of adjacent H3K27; epigenetic silencing of NRROS increased the stability of NOX2, instigating oxidative stress. The present study will utilize TRPM7 knockout mice and TRPM7 pharmacological blocker to explore the role of TRPM7 channel kinase in cerebrovascular remodeling during hypertension. The data yielded in the present study will evaluate the strategy of targeting TRPM7 channel kinase for the treatment of stroke.