Buyang Huanwu Decoction in Inhibiting Pathological Vascular Remodeling Through the TGFBR1 Signaling Pathway

Abstract

Background: The occurrence and progression of atherosclerosis (AS) are closely intertwined with pathological vascular remodeling that shows the key manifestations of migration, proliferation, and neointimal hyperplasia (NIH) of vascular smooth muscle cells (VSMCs). Buyang Huanwu decoction (BYHWD), which is comprised by traditional Chinese medicinal herbs, exhibits certain therapeutic effects on AS. Nevertheless, the precise effects and the fundamental mechanisms of BYHWD on the migration, proliferation, and NIH of VSMCs remain to be further explored.Purpose: The present work aimed to analyze the impact of BYHWD on NIH and explore the possible influence of the Transforming Growth Factor Beta Receptor 1 (TGFBR1) on mediating the function of BYHWD in inhibiting vascular remodeling.Methods: The influence of BYHWD on migration and proliferation of mouse vascular smooth muscle cells (MOVAS) and human aortic smooth muscle cells (HASMCs) was assessed through MTT, EdU, Transwell, wound healing, and Western blot (WB) assays. In addition, the role of BYHWD was further validated using the TGFBR1-encoding adenovirus vector. In vivo, the impact of BYHWD on intimal formation and TGFBR1 activation was determined based on the adeno-associated virus mediated TGFBR1 overexpression models and a left common carotid artery (LCCA) ligation mouse model.Results: BYHWD dose-dependently suppressed VSMCs migration and proliferation, which included inhibiting cyclin A2, CDK4, MMP9, and TIMP1 expression. Additionally, p-TGFBR1, p-Smad2, and p-Smad3 expression decreased after BYHWD administration, while their phosphorylation levels were partially reversed by the overexpression of TGFBR1. Similarly, the inhibition of BYHWD against VSMCs migration and proliferation were partially mitigated by the overexpression of TGFBR1. Furthermore, BYHWD significantly attenuated NIH and decreased the p-TGFBR1, p-Smad2, and p-Smad3 levels in LCCA model; however, such inhibitory effect could be partially reversed through the overexpression of TGFBR1.Conclusion: This study provides initial evidence supporting that BYHWD blocks VSMCs migration, proliferation, and NIH by suppressing TGFBR1 pathway. BYHWD is promising to become a candidate treatment strategy for AS and pathological vascular remodeling.

Note:
Funding Declaration: The present work was funded by the National Natural Science Foundation of China, China (Nos. 81973645, 82274417, 82204959, 82104968, 82305225), Science and Technology Project of Guangzhou City, China (202201011196), Dongguan Science and Technology of Social Development Program (20231800932382), Guangdong Basic and Applied Basic Research Foundation, China (Nos. 2022A1515011630, 2022A1515110870, 2021A1515220010, 2021A1515110786, 2021A1515011707, 2022A1515110870).

Conflicts of Interest: None.

Ethical Approval: Our animal experimental protocols gained approval from the Animal Ethics Committee of Southern Medical University and performed according to guidelines for the care and use of laboratory animals released by the National Institutes of Health. The Ethical Review Number is SMUL2023004.

Keywords: Buyang Huanwu decoction, VSMCs, Pathological vascular remodeling, Migration, Proliferation, Neointimal Hyperplasia, TGFBR1