Protection of Angiotensin II–Induced Vascular Hypertrophy in Vascular Smooth Muscle–Targeted Receptor Activity-Modifying Protein 2 Transgenic Mice

Abstract

Abstract-The vasodilator and vascular regulatory peptide adrenomedullin (AM), a member of the calcitonin gene-related peptide family of peptides, is predicted to play a pivotal protective role in cardiovascular dysfunction. The principle AM (AM1) receptor is composed of a G protein-linked calcitonin receptor-like receptor and a receptor activity-modifying protein (receptor activity-modifying protein 2). There is little knowledge of the receptors via which AM acts in diseases. Using smooth muscle-targeted receptor activity-modifying protein 2 transgenic mice with increased vascular density of functional AM1 receptors, we demonstrate that receptor activity-modifying protein 2 transgenic mice are not protected against angiotensin II-induced hypertension or cardiac hypertrophy. However, vascular hypertrophy, together with vascular cell adhesion molecule 1 and monocyte chemotactic protein 1 expression, is significantly reduced in the aortic walls of transgenic mice, as determined by histological techniques. This indicates that the AM1 vascular smooth muscle receptor can mediate local protection in vivo. This is supported by proliferation studies in cultured smooth muscle cells. By comparison, levels of hypotension and inflammation in a shock model were similar to those in wild-type mice. Thus, a role of the AM1 receptor in the vasoactive component could not be detected, and evidence is provided to show that the hypotensive response to AM is subject to desensitization in vivo. The finding that the vascular smooth muscle AM1 receptor acts at a local level to protect against hypertension-induced vascular hypertrophy and inflammation provides evidence that targeting this receptor may be a beneficial therapeutic approach. A drenomedullin (AM) is a member of the calcitonin gene-related peptide (CGRP) family of peptides that includes intermedin and amylin. 1 AM and CGRP possess potent vasodilator activity, and AM is Ϸ10 to 100 times less potent than CGRP. However, there is also strong evidence showing that AM possesses vascular development and remodeling properties. [2][3][4][5][6] It is considered to play a pivotal role in cardiovascular regulation. AM expression is upregulated in vascular tissues in response to inflammatory cytokines 7 and hypoxia. 8 Moreover, plasma levels are raised in cardiovascular conditions that include heart failure and sepsis. 1,9,10 Studies in AM transgenics and heterozygous knockouts have revealed a protective function of this peptide, 3 as shown in sepsis, 4,11 and collateral vessel development in ischemia. 12 Furthermore, beneficial effects of exogenous AM were detected in ischemia, hypovolemic shock, and endotoxemia. [13][14][15][16] Thus, upregulation of the peptide correlates with important cardiovascular activities, although little is known about the receptors involved in these responses.Receptors for AM and CGRP constitute a unique family of G protein-linked receptors. They consist of the calcitonin receptor-like receptor (CL) with 7 transmembrane domains and 1 of 3 associated receptor-ac...

Receptor Activity-Modifying Protein-1 Augments Cerebrovascular Responses to Calcitonin Gene-Related Peptide and Inhibits Angiotensin II-Induced Vascular Dysfunction

“…The present results indicate that Ang II produced superoxide-mediated vascular dysfunction in control mice and show for the first time that this effect was prevented in hRAMP1 transgenic mice. Related to these findings, overexpression of RAMP2 in another transgenic mouse protects against vascular inflammation and hypertrophy in a model of Ang II-dependent hypertension 36. Collectively, these findings support the emerging concept that members of the RAMP protein family may protect the vasculature from Ang II.…”

Endothelial Restoration of Receptor Activity–Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy

“…Moreover, the reduced basal blood pressure of Ramp2 −/− Tg mice was observed without the exogenous administration of the canonical, hypotensive ligand AM, which was previously required to lower blood pressures in a vSMC-specific overexpression model of Ramp2. 21, 22 …”

Regulation of myofibroblast differentiation and bleomycin-induced pulmonary fibrosis by adrenomedullin

“…C57/B6 mice with a RAMP2 transgene under the control of the smooth muscle actin promoter (TG-RAMP2) were kindly provided by Dr. Walter Born and were used previously (32,55). Eight-to ten-week-old WT or Tg-RAMP2 mice weighing 25 g were intratracheally instilled with 1 U/kg bleomycin (Bleocip, Cipla).…”