Division of Nephrology, Department of Medicine, McMaster University, Hamilton, ON, Canada.
Hypertens Res. 2024 Nov;47(11):3158-3172. doi: 10.1038/s41440-024-01872-8. Epub 2024 Sep 19.
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.
高血压的特征是氧化应激和纤维化驱动的阻力动脉重塑。我们之前的研究表明，激活素 A 拮抗剂，卵泡抑素，可抑制高血压慢性肾脏病模型中的肾氧化应激和纤维化。在这里，我们研究了卵泡抑素对原发性和继发性高血压模型中血压和血管结构与功能的影响。5/6 肾切除术小鼠，一种继发性高血压模型，用外源性卵泡抑素或卵泡抑素 miRNA 抑制剂处理 9 周，以增加内源性卵泡抑素。通过尾套测量小鼠血压。自发性高血压大鼠，一种原发性高血压模型，用卵泡抑素治疗 8 周。Wistar Kyoto（WKY）大鼠用作正常血压对照。通过无线电遥测测量大鼠血压。分离小鼠肠系膜上动脉和大鼠第一分支肠系膜动脉进行结构和功能分析。在这两种模型中，卵泡抑素均显著降低血压并改善血管结构，减少中膜厚度和胶原含量。卵泡抑素还降低了激动剂诱导的最大收缩，并改善了内皮依赖性松弛。两种模型中，卵泡抑素均减轻了血管氧化应激。在离体 WKY 血管中，激活素 A 增加了氧化应激，增强了收缩，并降低了内皮依赖性松弛。抑制氧化应激恢复了血管松弛。本研究表明，卵泡抑素可降低原发性和继发性高血压模型中的血压并改善血管结构和功能。作用可能是通过其抑制激活素 A 和氧化应激介导的。这些数据表明，卵泡抑素作为一种新型抗高血压药物具有潜在的治疗作用。卵泡抑素通过拮抗激活素 A，抑制氧化应激，改善原发性和继发性 HTN 模型阻力动脉的结构和功能。FST 降低胶原含量和血管 ROS。功能上，FST 改善内皮依赖性松弛并降低最大血管收缩。两种模型中，阻力动脉结构和功能的改善与血压的降低相关。
