Su Chenlin, Mi Xinya, Ito Tomoya, Kato Yuri, Nishimura Akiyuki, Nagata Ryu, Mori Yasuo, Nishida Motohiro
Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
National Institute for Physiological Science (NIPS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
Biomolecules. 2025 Feb 12;15(2):267. doi: 10.3390/biom15020267.
Vascular smooth muscle cells (VSMCs) can dynamically change their phenotype between contractile and synthetic forms in response to environmental stress, which is pivotal in maintaining vascular homeostasis and mediating pathological remodeling of blood vessels. We previously reported that suppression of canonical transient receptor potential 6 (TRPC6) channel-mediated cation entry sustains VSMCs contractile phenotype and promotes the blood flow recovery after hindlimb ischemia in mice. We also reported that Zn, a metal biomolecule mobilized by TRPC6 channel activation, exerts potential beneficial effects on cardiac contractility and remodeling. Therefore, we hypothesized that TRPC6-mediated Zn influx participates in phenotype switching of VSMCs and vascular remodeling. We established rat aortic smooth muscle cells (RAoSMCs) stably expressing wild type (WT) and Zn only impermeable TRPC6 (KYD) mutant. Although the resting phenotypes were similar in both RAoSMCs, pharmacological TRPC6 activation by PPZ2 prevented the transforming growth factor (TGF) β-induced reduction in the intracellular Zn amount and contractile differentiation in RAoSMCs (WT), but failed to prevent them in RAoSMCs (KYD). There were no significant differences in TRPC6-dependent cation currents among all RAoSMCs pretreated with or without TGFβ and/or PPZ2, suggesting that TRPC6 channels are functionally expressed in RAoSMCs regardless of their phenotype. Treatment of mice with PPZ2 attenuated the progression of vascular remodeling caused by chronic angiotensin II infusion. These results suggest that Zn influx through TRPC6 channels negatively regulates the TGFβ-induced contractile differentiation of VSMCs and the progression of vascular remodeling in rodents.
血管平滑肌细胞（VSMCs）可根据环境应激在收缩型和合成型之间动态改变其表型，这对维持血管稳态和介导血管病理重塑至关重要。我们之前报道过，抑制经典瞬时受体电位6（TRPC6）通道介导的阳离子内流可维持VSMCs的收缩表型，并促进小鼠后肢缺血后的血流恢复。我们还报道过，锌是一种由TRPC6通道激活而动员的金属生物分子，对心脏收缩性和重塑具有潜在的有益作用。因此，我们推测TRPC6介导的锌内流参与VSMCs的表型转换和血管重塑。我们建立了稳定表达野生型（WT）和仅对锌不可渗透的TRPC6（KYD）突变体的大鼠主动脉平滑肌细胞（RAoSMCs）。尽管两种RAoSMCs的静息表型相似，但PPZ2对TRPC6的药理学激活可防止转化生长因子（TGF）β诱导的RAoSMCs（WT）细胞内锌含量降低和收缩分化，但在RAoSMCs（KYD）中未能防止这种情况。在用或不用TGFβ和/或PPZ2预处理的所有RAoSMCs中，TRPC6依赖性阳离子电流没有显著差异，这表明无论其表型如何，TRPC6通道在RAoSMCs中均有功能表达。用PPZ2处理小鼠可减轻慢性输注血管紧张素II引起的血管重塑进展。这些结果表明，通过TRPC6通道的锌内流对TGFβ诱导的VSMCs收缩分化和啮齿动物血管重塑进展具有负调节作用。
