The role of the adrenomedullin receptor (CL/RAMP2) in vascular hypertrophy

Lihuan Liang1, Christina Tam1, Gabor Pozsgai1, Knut Husman2, Walter Born2, Jan Fischer2, Robin Poston1, Ajay Shah1, Susan Brain1. 1King’s College London, London, United Kingdom, 2University of Zurich, Zurich, Switzerland.

Levels of the CGRP-like peptide adrenomedullin (AM) are raised in hypertension. However, there is little knowledge of the receptors via which AM acts on in disease. In this study we have examined a murine model of hypertension using smooth muscle cell-targeted RAMP2 overexpressing transgenic (TG) mice and respective wildtypes (WT). Angiotensin II (0.9 mg/kg/day) or vehicle (0.01% 10 mM acetic acid in saline) was infused for 14 days via pre-implanted osmotic mini-pumps according to UK law and local ethics guidelines. We monitored the blood pressure, and measured aortic wall width and area. The mean arterial blood pressure was, by day 14, similar between wild type (WT) and RAMP2 TG mice that had received angiotensin II and significantly greater than that of mice which received saline (WT saline 122.1.8±5.3mmHg; WT Ang II 145.4±7.0mmHg; RAMP2 TG saline 117.7±5.7mmHg; RAMP2 TG Ang II 147.1±7.4mmHg, n =8-10). However, a significant increase (p<0.001) in aortic wall width and area was observed in angiotensin II-treated WT mice (aortic wall width: increased from 50±3μm to 75±3μm, n=8-9 sections from 3 mice in each case), but not in RAMP2 TG mice (from 50±5μm to 50±3μm, n=8-9 sections from 3 mice in each case), as determined by histology. We also used immunohistochemistry to examine the expression of the adhesion molecule VCAM-1 in the aortic wall. The VCAM-1 expression in smooth muscle cells of RAMP2 TG hypertensive mice was significantly reduced (p<0.001) when compared with WT hypertensive mice (aortic area percentage of VCAM-1 expression in hypertensive mice: WT 42.3 ± 3.2%; TG 8.9 ± 3.4%, mean ± SEM; n=5). Thus, we hypothesize that RAMP2 TG mice are protected against chronic angiotensin II-induced aortic wall hypertrophy, and this may be related to decreased expression of VCAM-1. These findings also indicate that the AM1 vascular smooth muscle receptor can mediate local protective effects in vivo. The findings reveal an important protective role for the vascular smooth muscle AM1 receptor which may be a novel target for the treatment of vascular hypertrophy.

This study was supported by a BBSRC-led IMB capacity building award and by the BHF.