TRPC3 channel confers cerebrovascular remodelling during hypertension via transactivation of EGF receptor signalling
TRPC3 channel confers cerebrovascular remodelling during hypertension via transactivation of EGF receptor signalling
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DOI：
10.1093/cvr/cvv246
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发表时间：
2016-01-01
影响因子：
10.8
通讯作者：
Zhang, Zheng
中科院分区：
文献类型：
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作者：
Wang, Mi;Tang, Yong-Bo;Zhang, Zheng
血管平滑肌细胞的离子扰动参与了高血压脑血管重构，但瞬时受体电位（TRP）通道超家族的作用尚不清楚。本研究进行了定义的TRP通道脑血管remodeling.Methods和结果通过整合定量PCR，蛋白质印迹，膜片钳，和Ca 2 + imaging，我们确定TRP通道，亚家族典型，成员3（TRPC 3）作为通道亚型最显着升高的两肾，两夹卒中易感高血压大鼠的基底动脉。重要的是，TRPC 3通道阻滞剂吡唑3（Pyr 3）的给药可减弱脑血管重塑。在高血压期间，表皮生长因子受体（EGFR）被反式激活，表现为显著的EGFR磷酸化、pro-HB-EGF脱落增加和ADAM 17（HB-EGF脱落酶）活性升高。ADAM 17活性增加是由于激活增强而不是表达升高。值得注意的是，Pyr 3治疗抑制了高血压中的EGFR反式激活。在增殖的基底动脉平滑肌细胞或高血压大鼠的基底动脉，免疫共沉淀实验揭示了TRPC 3和ADAM 17之间的相互作用后，Ang II stimulation.Conclusion，我们表明，增强EGFR的反式激活，由于增加TRPC 3的表达和功能耦合的TRPC 3/ADAM 17，导致脑血管重塑。因此，TRPC 3诱导的EGFR反式激活可用于治疗，以防止高血压诱导的脑血管重塑。
Aims Ionic perturbation in vascular smooth muscle cells contributes to cerebrovascular remodelling in the setting of hypertension, but the role of transient receptor potential (TRP) channel superfamily remains unknown. The present study was conducted to define the contribution of TRP channels to cerebrovascular remodelling.Methods and Results By integrating quantitative PCR, western blotting, patch clamping, and Ca2+ imaging, we identified TRP channel, subfamily canonical, member 3 (TRPC3) as the channel subtype most considerably elevated in basilar arteries of two-kidney, two-clip stroke-prone hypertensive rats. Importantly, administration of pyrazole 3 (Pyr3), a TRPC3 channel blocker, attenuated cerebrovascular remodelling. During hypertension, epidermal growth factor receptor (EGFR) was transactivated, as evidenced by marked EGFR phosphorylation, increased pro-HB-EGF shedding, and elevated activity of ADAM17 (HB-EGF sheddase). ADAM17 activity was increased owing to enhanced activation rather than elevated expression. Remarkably, Pyr3 treatment suppressed EGFR transactivation in hypertension. In proliferating basilar artery smooth muscle cells or basilar arteries of hypertensive rats, co-immunoprecipitation assay revealed an interaction between TRPC3 and ADAM17 upon Ang II stimulation.Conclusion Collectively, we demonstrated that enhanced EGFR transactivation, due to increased TRPC3 expression and functional coupling of TRPC3/ADAM17, resulted in cerebrovascular remodelling. Therefore, TRPC3-induced EGFR transactivation may be therapeutically exploited to prevent hypertension-induced cerebrovascular remodelling.