ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Cardiovascular and Smooth Muscle Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1617420
HDL ATTENUATES ANG II-AT1R-EGFR SIGNALING AND REVERSES VASCULAR REMODELING IN SPONTANEOUSLY HYPERTENSIVE RATS
Provisionally accepted
- 1Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
- 2American International Universty, Jahra, Kuwait
- 3Qatar University, Doha, Qatar
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Background: Angiotensin II (Ang II) signaling via angiotensin II type 1 receptor (AT1R) and transactivation of epidermal growth factor receptor (EGFR) enhances vascular smooth muscle cell (VSMC) proliferation and contributes to vascular remodeling evident in spontaneously hypertensive rats (SHR) aorta. Although high-density lipoprotein (HDL) has been shown to lower blood pressure in SHR, the underlying mechanism(s) remain incompletely understood. We propose that HDL attenuates Ang II-AT1R-EGFR signaling and reverses vascular remodeling in SHR. Methods: Wistar Kyoto rats (WKY) and SHR were treated with HDL for one week. Vascular remodeling was histologically examined. VSMC proliferation and the expression levels of AT1R, EGFR, extracellular signal regulated kinases 1/2 (ERK1/2), scavenger receptor class B type-I (SR-BI) and its adaptor protein PDZK1 were examined by immunofluorescence. VSMC proliferation was further examined in vitro. Results: HDL treatment reduced blood pressure, increased the production of nitric oxide, increased aortic lumen diameter, reduced media thickness to lumen diameter ratio, decreased collagen contents in SHR. Furthermore, HDL treatment decreased the number of proliferating VSMCs and α-smooth muscle cell actin, reduced the expression of AT1R and EGFR and increased the expression of SR-BI adaptor protein, PDZK1, in SHR aortas. In isolated VSMCs, HDL attenuated Ang II-induced proliferation by reducing AT1R expression and decreasing Ang II-induced transactivation of EGFR. HDL effects were SR-BI dependent and were mimicked by different HDL subpopulations, reconstituted HDL, and lipid free apolipoprotein A-I. Conclusions: HDL attenuates Ang II-AT1R-EGFR signaling, reduces VSMC proliferation, and reverses vascular remodeling in SHR. HDL modulation of vascular remodeling could be one mechanism by which HDL reduces blood pressure in SHR.
Keywords: HDL, Angiotensin II, Sr-Bi, vascular remodeling, proliferation
Received: 24 Apr 2025; Accepted: 02 Jul 2025.
Copyright: © 2025 Aljarallah, Kalakh, Akhtar and Yousif. 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: Aishah Aljarallah, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
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