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Abstract <p>Transient receptor potential canonical 1 (TRPC1) channel, a Ca<sup>2+</sup>-permeable ion channel widely expressed in vasculature, has been reported to be involved in various cardiovascular disorders. However, the pathophysiological function of vascular smooth muscle cell (VSMC)-derived TRPC1 in hypertension and hypertensive cardiovascular remodeling remains to be defined. In this study, we found increased TRPC1 expression in both angiotensin II (AngII)-treated VSMCs and aortas from AngII-infused mice. VSMC-specific TRPC1 deficiency strikingly attenuated AngII-induced vasoconstriction, hypertension, vascular remodeling, and cardiac hypertrophy. Mechanistically, AngII activated enhancer of zeste homolog 2 (EZH2) to stimulate TRPC1 expression, induced calcium influx and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK), which in turn triggered VSMC proliferation and migration and exacerbated hypertension and cardiovascular remodeling. Treatment with EZH2 inhibitor reduced VSMC proliferation and migration and alleviated vasoconstriction and hypertension in AngII-infused mice. Together, we revealed the pathogenic role of the EZH2-TRPC1-MEK/ERK pathway in AngII-induced hypertension and cardiovascular damage. TRPC1 or EZH2 inhibition may represent a desirable therapeutic target for the treatment of hypertension.</p> Key messages <p><UnorderedList Mark="Bullet"> <ItemContent> <p>AngII activates AT1R-EZH2-TRPC1 pathway in VSMCs and aortas of hypertensive mice.</p> </ItemContent> <ItemContent> <p>TRPC1 promotes VSMC proliferation and migration via MEK/ERK signaling.</p> </ItemContent> <ItemContent> <p>Inhibition of TRPC1 or EZH2 alleviates hypertension and cardiovascular remodeling.</p> </ItemContent> </UnorderedList></p>

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VSMC-specific TRPC1 deletion attenuates angiotensin II-induced hypertension and cardiovascular remodeling

  • 期刊论文

  • 发表日期：

    2025年1月2日

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  • Xin Wen,
  • Yuefeng Peng,
  • Wenqing Yang,
  • Yuzhong Zhu,
  • Fan Yu,
  • Li Geng,
  • Xianfeng Wang,
  • Xiaoyan Wang,
  • Xiaodong Zhang,
  • Yi Tang,
  • Lei Feng,
  • Tingting Zhou,
  • Hongliang Jia,
  • Liu Yang

摘要

Abstract

Transient receptor potential canonical 1 (TRPC1) channel, a Ca2+-permeable ion channel widely expressed in vasculature, has been reported to be involved in various cardiovascular disorders. However, the pathophysiological function of vascular smooth muscle cell (VSMC)-derived TRPC1 in hypertension and hypertensive cardiovascular remodeling remains to be defined. In this study, we found increased TRPC1 expression in both angiotensin II (AngII)-treated VSMCs and aortas from AngII-infused mice. VSMC-specific TRPC1 deficiency strikingly attenuated AngII-induced vasoconstriction, hypertension, vascular remodeling, and cardiac hypertrophy. Mechanistically, AngII activated enhancer of zeste homolog 2 (EZH2) to stimulate TRPC1 expression, induced calcium influx and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK), which in turn triggered VSMC proliferation and migration and exacerbated hypertension and cardiovascular remodeling. Treatment with EZH2 inhibitor reduced VSMC proliferation and migration and alleviated vasoconstriction and hypertension in AngII-infused mice. Together, we revealed the pathogenic role of the EZH2-TRPC1-MEK/ERK pathway in AngII-induced hypertension and cardiovascular damage. TRPC1 or EZH2 inhibition may represent a desirable therapeutic target for the treatment of hypertension.

Key messages

AngII activates AT1R-EZH2-TRPC1 pathway in VSMCs and aortas of hypertensive mice.

TRPC1 promotes VSMC proliferation and migration via MEK/ERK signaling.

Inhibition of TRPC1 or EZH2 alleviates hypertension and cardiovascular remodeling.