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Follistatin lowers blood pressure and improves vascular structure and function in essential and secondary hypertension

Hypertension Research volume 47, pages 3158–3172 (2024)Cite this article

A Comment to this article was published on 17 October 2024

Abstract

Hypertension is characterized by resistance artery remodeling driven by oxidative stress and fibrosis. We previously showed that an activin A antagonist, follistatin, inhibited renal oxidative stress and fibrosis in a model of hypertensive chronic kidney disease. Here, we investigate the effects of follistatin on blood pressure and vascular structure and function in models of essential and secondary hypertension. 5/6 nephrectomised mice, a model of secondary hypertension, were treated with either exogenous follistatin or with a follistatin miRNA inhibitor to increase endogenous follistatin for 9 weeks. Blood pressure in mice was measured by tail cuff. Spontaneously hypertensive rats, a model of essential hypertension, were treated with follistatin for 8 weeks. Wistar Kyoto (WKY) rats were used as the normotensive control. Blood pressure in rats was measured by radiotelemetry. Mouse superior mesenteric arteries and rat first branch mesenteric arteries were isolated for structural and functional analyses. In both models, follistatin significantly lowered blood pressure and improved vascular structure, decreasing medial thickness and collagen content. Follistatin also reduced agonist-induced maximum contraction and improved endothelium-dependent relaxation. Increased vessel oxidative stress was attenuated by follistatin in both models. In ex vivo WKY vessels, activin A increased oxidative stress, augmented constriction, and decreased endothelium-dependent relaxation. Inhibition of oxidative stress restored vessel relaxation. This study demonstrates that follistatin lowers blood pressure and improves vascular structure and function in models of essential and secondary hypertension. Effects were likely mediated through its inhibition of activin A and oxidative stress. These data suggest a potential therapeutic role for follistatin as a novel antihypertensive agent.

Follistatin, through antagonization of activin A, inhibits oxidative stress and improves vascular structure and function in resistance arteries from models of essential and secondary HTN. FST decreases collagen content and vascular ROS. Functionally, FST improves endothelium-dependent relaxation and decreases maximal vasoconstriction. Improved resistance artery structure and function are correlated with a decrease in BP in both models.

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Acknowledgements

The authors acknowledge the support of St. Joseph’s Healthcare Hamilton for nephrology research. They are also grateful to Paranta Biosciences Limited (Australia) for providing human recombinant FST-288.

Funding

This work was supported by the Heart and Stroke Foundation (G-19-0024347).

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Author notes

  1. These authors contributed equally: Ann Kuganathan, Marcos Leal.

  2. These authors jointly supervised this work: Jeffrey Dickhout, Joan C. Krepinsky.

Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON, Canada

    Ann Kuganathan, Marcos Leal, Neel Mehta, Vincent Lu, Bo Gao, Melissa MacDonald, Jeffrey Dickhout & Joan C. Krepinsky

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Correspondence to Joan C. Krepinsky.

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Kuganathan, A., Leal, M., Mehta, N. et al. Follistatin lowers blood pressure and improves vascular structure and function in essential and secondary hypertension. Hypertens Res 47, 3158–3172 (2024). https://doi.org/10.1038/s41440-024-01872-8

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