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

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Hypertension Research

Background:

• Transient receptor potential canonical 1 (TRPC1) channels are Ca2+-permeable ion channels found in vasculature.
• The role of TRPC1 specifically from vascular smooth muscle cells (VSMCs) in hypertension and cardiac remodeling is not fully understood.

Purpose of the Study:

• To investigate the pathophysiological role of VSMC-derived TRPC1 in angiotensin II (AngII)-induced hypertension and cardiovascular remodeling.
• To elucidate the molecular mechanisms linking AngII, TRPC1, and hypertensive cardiovascular damage.

Main Methods:

• Assessed TRPC1 expression in AngII-treated VSMCs and mouse aortas.
• Utilized VSMC-specific TRPC1-deficient mice to evaluate AngII-induced effects.
• Investigated the role of enhancer of zeste homolog 2 (EZH2) and the MEK-ERK pathway in mediating TRPC1 function.
• Administered EZH2 inhibitors to assess therapeutic efficacy.

Main Results:

• Increased TRPC1 expression was observed in AngII-treated VSMCs and aortas.
• VSMC-specific TRPC1 deficiency attenuated AngII-induced vasoconstriction, hypertension, vascular remodeling, and cardiac hypertrophy.
• AngII activated EZH2, leading to increased TRPC1 expression, calcium influx, and MEK-ERK activation, promoting VSMC proliferation and migration.
• EZH2 inhibition reduced VSMC proliferation/migration and alleviated hypertension and vasoconstriction.

Conclusions:

• The EZH2-TRPC1-MEK/ERK pathway plays a critical role in AngII-induced hypertension and cardiovascular damage.
• TRPC1 in VSMCs contributes significantly to hypertensive vascular and cardiac remodeling.
• Targeting TRPC1 or EZH2 presents a potential therapeutic strategy for hypertension.