Follistatin lowers blood pressure and improves vascular structure and function in essential and secondary
Ann Kuganathan1, Marcos Leal1, Neel Mehta1
1Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON, Canada.
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.
Insights
Follistatin, an activin A antagonist, effectively lowers blood pressure and improves vascular health in hypertension models. This suggests its potential as a novel antihypertensive therapy by reducing oxidative stress and fibrosis.
Area of Science:
- Cardiovascular Research
- Nephrology
- Endocrinology
Background:
- Hypertension involves resistance artery remodeling driven by oxidative stress and fibrosis.
- Previous studies indicated follistatin inhibits renal oxidative stress and fibrosis in chronic kidney disease models.
Purpose of the Study:
- To investigate the effects of follistatin on blood pressure, vascular structure, and function in models of essential and secondary hypertension.
- To explore the therapeutic potential of follistatin as an antihypertensive agent.
Main Methods:
- Follistatin treatment in 5/6 nephrectomized mice (secondary hypertension) and spontaneously hypertensive rats (essential hypertension).
- Blood pressure measurement via tail cuff and radiotelemetry.
- Vascular structural and functional analyses of mesenteric arteries.
- Assessment of oxidative stress and activin A effects in isolated vessels.
Main Results:
- Follistatin significantly lowered blood pressure in both hypertension models.
- Improved vascular structure, including decreased medial thickness and collagen content.
- Reduced maximal contraction and enhanced endothelium-dependent relaxation.
- Attenuated vessel oxidative stress, with activin A shown to increase oxidative stress and impair relaxation.
Conclusions:
- Follistatin demonstrates antihypertensive effects by improving vascular structure and function in essential and secondary hypertension models.
- The mechanism involves antagonizing activin A and inhibiting oxidative stress.
- Follistatin shows promise as a novel therapeutic agent for hypertension.
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