Fluoride-induced hypertension by regulating RhoA/ROCK pathway and phenotypic transformation of vascular smooth muscle cells: In vitro and in vivo evidence

Wenjing Yang; Chunqing Lu; Fang Chu; Keming Bu; Hao Ma; Qiaoyu Wang; Zhe Jiao; Sheng Wang; Xiyue Yang; Yanhui Gao; Dianjun Sun; Hongna Sun

Ecotoxicology and Environmental Safety (Aug 2024)

Fluoride-induced hypertension by regulating RhoA/ROCK pathway and phenotypic transformation of vascular smooth muscle cells: In vitro and in vivo evidence

Wenjing Yang,
Chunqing Lu,
Fang Chu,
Keming Bu,
Hao Ma,
Qiaoyu Wang,
Zhe Jiao,
Sheng Wang,
Xiyue Yang,
Yanhui Gao,
Dianjun Sun,
Hongna Sun

Affiliations

Wenjing Yang: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China
Chunqing Lu: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China
Fang Chu: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China
Keming Bu: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China
Hao Ma: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China
Qiaoyu Wang: NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China; Teaching Center of Morphology, School of Basic Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, China
Zhe Jiao: NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China; Institute for Kashin Beck Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin 150081, China
Sheng Wang: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China
Xiyue Yang: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China
Yanhui Gao: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China
Dianjun Sun: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China
Hongna Sun: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China; NHC Key Laboratory of Etiology and Epidemiology (Harbin Medical University) Heilongjiang Provincial Key Laboratory of Trace Elements and Human Health, Key Laboratory of Etiology and Epidemiology, Education Bureau of Heilongjiang Province, State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), China; Corresponding author at: Institute for Endemic Fluorosis Control, Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Harbin Medical University, Harbin, Heilongjiang 150081, China.

Journal volume & issue: Vol. 281
p. 116681

Abstract

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Fluoride exposure has been implicated as a potential risk factor for hypertension, but the underlying mechanisms remain unclear. This study investigated the role of the RhoA/ROCK signaling pathway in fluoride-induced hypertension. Male Wistar rats were divided into different groups and exposed to varying concentrations of sodium fluoride (NaF) or sodium chloride (NaCl) via drinking water. The rats’ blood pressure was measured, and their aortic tissue was utilized for high-throughput sequencing analysis. Additionally, rat and A7r5 cell models were established using NaF and/or Fasudil. The study evaluated the effects of fluoride exposure on blood pressure, pathological changes in the aorta, as well as the protein/mRNA expression levels of phenotypic transformation indicators (a-SMA, calp, OPN) in vascular smooth muscle cells (VSMCs), along with the RhoA/ROCK signaling pathway (RhoA, ROCK1, ROCK2, MLC/p-MLC). The results demonstrated that fluoride exposure in rats led to increased blood pressure. High-throughput sequencing analysis revealed differential gene expression associated with vascular smooth muscle contraction, with the RhoA/ROCK signaling pathway emerging as a key regulator. Pathological changes in the rat aorta, such as elastic membrane rupture and collagen fiber deposition, were observed following NaF exposure. However, fasudil, a ROCK inhibitor, mitigated these pathological changes. Both in vitro and in vivo models confirmed the activation of the RhoA/ROCK signaling pathway and the phenotypic transformation of VSMCs from a contractile to a synthetic state upon fluoride exposure. Fasudil effectively inhibited the activities of ROCK1 and ROCK2 and attenuated the phenotypic transformation of VSMCs. In conclusion, fluoride has the potential to induce hypertension through the activation of the RhoA/ROCK signaling pathway and phenotypic changes in vascular smooth muscle cells. These results provide new insights into the mechanism of fluoride-induced hypertension.

Published in Ecotoxicology and Environmental Safety

ISSN: 0147-6513 (Print); 1090-2414 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Technology: Environmental technology. Sanitary engineering: Environmental pollution; Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/ecotoxicology-and-environmental-safety

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