TRPC6-Mediated Zn<sup>2+</sup> Influx Negatively Regulates Contractile Differentiation of Vascular Smooth Muscle Cells
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 suppressio...
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2025-02-01
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| author | Chenlin Su Xinya Mi Tomoya Ito Yuri Kato Akiyuki Nishimura Ryu Nagata Yasuo Mori Motohiro Nishida |
| author_facet | Chenlin Su Xinya Mi Tomoya Ito Yuri Kato Akiyuki Nishimura Ryu Nagata Yasuo Mori Motohiro Nishida |
| author_sort | Chenlin Su |
| collection | DOAJ |
| description | 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<sup>2+</sup>, a metal biomolecule mobilized by TRPC6 channel activation, exerts potential beneficial effects on cardiac contractility and remodeling. Therefore, we hypothesized that TRPC6-mediated Zn<sup>2+</sup> 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<sup>2+</sup> 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<sup>2+</sup> 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<sup>2+</sup> influx through TRPC6 channels negatively regulates the TGFβ-induced contractile differentiation of VSMCs and the progression of vascular remodeling in rodents. |
| format | Article |
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| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-c67e61f4815a4eefb8bec0d4009787702025-08-20T02:44:31ZengMDPI AGBiomolecules2218-273X2025-02-0115226710.3390/biom15020267TRPC6-Mediated Zn<sup>2+</sup> Influx Negatively Regulates Contractile Differentiation of Vascular Smooth Muscle CellsChenlin Su0Xinya Mi1Tomoya Ito2Yuri Kato3Akiyuki Nishimura4Ryu Nagata5Yasuo Mori6Motohiro Nishida7Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, JapanGraduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, JapanGraduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, JapanGraduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, JapanNational Institute for Physiological Science (NIPS), National Institutes of Natural Sciences, Okazaki 444-8787, JapanGraduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, JapanGraduate School of Engineering, Kyoto University, Kyoto 615-8510, JapanGraduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, JapanVascular 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<sup>2+</sup>, a metal biomolecule mobilized by TRPC6 channel activation, exerts potential beneficial effects on cardiac contractility and remodeling. Therefore, we hypothesized that TRPC6-mediated Zn<sup>2+</sup> 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<sup>2+</sup> 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<sup>2+</sup> 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<sup>2+</sup> influx through TRPC6 channels negatively regulates the TGFβ-induced contractile differentiation of VSMCs and the progression of vascular remodeling in rodents.https://www.mdpi.com/2218-273X/15/2/267Zn<sup>2+</sup> influxTRPC6 channelphenotypic switchingvascular smooth muscle cells |
| spellingShingle | Chenlin Su Xinya Mi Tomoya Ito Yuri Kato Akiyuki Nishimura Ryu Nagata Yasuo Mori Motohiro Nishida TRPC6-Mediated Zn<sup>2+</sup> Influx Negatively Regulates Contractile Differentiation of Vascular Smooth Muscle Cells Biomolecules Zn<sup>2+</sup> influx TRPC6 channel phenotypic switching vascular smooth muscle cells |
| title | TRPC6-Mediated Zn<sup>2+</sup> Influx Negatively Regulates Contractile Differentiation of Vascular Smooth Muscle Cells |
| title_full | TRPC6-Mediated Zn<sup>2+</sup> Influx Negatively Regulates Contractile Differentiation of Vascular Smooth Muscle Cells |
| title_fullStr | TRPC6-Mediated Zn<sup>2+</sup> Influx Negatively Regulates Contractile Differentiation of Vascular Smooth Muscle Cells |
| title_full_unstemmed | TRPC6-Mediated Zn<sup>2+</sup> Influx Negatively Regulates Contractile Differentiation of Vascular Smooth Muscle Cells |
| title_short | TRPC6-Mediated Zn<sup>2+</sup> Influx Negatively Regulates Contractile Differentiation of Vascular Smooth Muscle Cells |
| title_sort | trpc6 mediated zn sup 2 sup influx negatively regulates contractile differentiation of vascular smooth muscle cells |
| topic | Zn<sup>2+</sup> influx TRPC6 channel phenotypic switching vascular smooth muscle cells |
| url | https://www.mdpi.com/2218-273X/15/2/267 |
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