# HDL attenuates Ang II–AT1R–EGFR signaling and reverses vascular remodeling in spontaneously hypertensive rats

## TL;DR

This study shows that HDL reduces high blood pressure in hypertensive rats by reversing harmful changes in blood vessels and blocking harmful signaling pathways.

## Contribution

The study reveals a novel mechanism by which HDL lowers blood pressure through attenuation of Ang II–AT1R–EGFR signaling and reversal of vascular remodeling.

## Key findings

- HDL treatment reduced blood pressure and vascular remodeling in spontaneously hypertensive rats.
- HDL inhibited VSMC proliferation and reduced the expression of AT1R and EGFR.
- HDL effects were mediated through SR-BI and were mimicked by different HDL subpopulations.

## Abstract

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.

Wistar Kyoto rats (WKY) and SHR were treated with HDL for 1 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.

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 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.

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.

HDL treatment attenuates Ang II-AT1R-EGFR signaling, reversing vascular remodeling in hypertensive rats. Methods show in vivo HDL administration. Results indicate increased lumen diameter, decreased media thickness to lumen diameter ratio, collagen, and VSMC proliferation, with reduced blood pressure. Mechanism involves HDL-mediated inhibition of VSMCs proliferation through SR-BI, impacting AT1R and EGFR signaling. Conclusions highlight HDL's role in reducing VSMCs proliferation, reversing vascular remodeling, and lowering blood pressure.