ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Ethnopharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1621700
Pterostilbene mitigates experimental pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition
Provisionally accepted
- Qilu Hospital, Shandong University, Jinan, China
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Background: The natural compound pterostilbene (PTE) has multiple cardiovascular protective effects. However, its effects on pulmonary arterial hypertension (PAH)-associated vascular remodeling remain to be elucidated. This study investigated the effects of PTE on monocrotaline (MCT)-induced PAH in rats in vivo and explored the underlying molecular mechanisms in human primary pulmonary arterial endothelial cells (hPAECs) in vitro. Methods: Experimental PAH was established by subcutaneous injection of MCT (50 mg/kg) in Sprague-Dawley rats, which were then randomly divided into vehicle or PTE (15 mg/kg via gavage) treatment groups. Endothelial-to-mesenchymal transition (EndMT) was modeled in hPAECs by treating with transforming growth factor-β, tumor necrosis factor-α, and interleukin-1β in combination. Results: In rats with MCT-induced PAH, administration of PTE resulted in a reduction in right ventricular systolic pressure, thereby alleviating right ventricular hypertrophy. This was accompanied by mitigation of the remodeling of pulmonary arteries. In vitro, genome-wide mRNA sequencing identified that PTE significantly downregulated the expression of high mobility group AT-hook 2 (HMGA2), a transcription factor involved in the pathogenesis of EndMT. Further, we demonstrated that PTE attenuated EndMT-related changes, including (1) reduced expression of the endothelial cell-specific markers platelet and endothelial cell adhesion molecule 1, and von Willebrand factor; (2) reduced nitric oxide production; and (3) increased expression of smooth muscle α-actin and other pro-fibrotic genes. Finally, we confirmed in vivo that PTE treatment reduced the expression of HMGA1/2 and Snai1/2 (markers of EndMT), and restored the expression of von Willebrand factor in the lungs of PAH rats.Conclusion: PTE mitigates MCT-induced PAH and vascular remodeling in rats, at least in part, by inhibiting HMGA-mediated EndMT, suggesting that PTE may be a useful complementary medicine in the treatment of PAH.
Keywords: pterostilbene, pulmonary arterial hypertension, Endothelial-to-mesenchymal transition, high mobility group AT-hook, SNAI, Twist
Received: 02 May 2025; Accepted: 03 Jun 2025.
Copyright: © 2025 Wang, Zhang, Liu, Jiang, Cui and Lu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Weida Lu, Qilu Hospital, Shandong University, Jinan, China
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