Regulation of cardiovascular development and homeostasis by the adrenomedullin-RAMP system.

Abstract

Adrenomedullin (AM), a member of the calcitonin peptide superfamily, is a peptide involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. Its receptor, calcitonin receptor-like receptor (CLR), associates with an accessory protein, receptor activity-modifying protein (RAMP). Depending upon which the three RAMP isoforms (RAMP1-3) it interacts with, CLR functions as a receptor for AM or other calcitonin family peptides. AM knockout mice (-/-) died mid-gestation due to abnormalities in vascular development. We found that phenotypes similar to AM-/- were reproduced only in RAMP2-/- mice. We generated endothelial cell-specific RAMP2 knockout mice (E-RAMP2-/-) and found most E-RAMP2-/- mice died perinatally. In surviving adults, vasculitis and organ fibrosis occurred spontaneously. We next generated drug-inducible cardiac myocyte-specific RAMP2-/- (DI-C-RAMP2-/-) mice, which exhibited dilated cardiomyopathy-like heart failure with cardiac dilatation and myofibril disruption. DI-C-RAMP2-/- hearts also showed changes in mitochondrial structure and downregulation of mitochondria-related genes involved in oxidative phosphorylation and β-oxidation. In contrast to RAMP2-/- mice, RAMP3-/- mice were born with no major abnormalities. In adult RAMP3-/- mice, postnatal angiogenesis was normal, but drainage of subcutaneous lymphatic vessels was delayed. RAMP3-/- mice also showed more severe interstitial edema than in wild-type mice in a tail lymphedema model. These findings show that the AM-RAMP system is a key determinant of cardiovascular integrity and homeostasis from prenatal stages through adulthood. The AM-RAMP2 system mainly regulates vascular development and homeostasis, while the AM-RAMP3 system mainly regulates lymphatic function in adults. The AM-RAMP system may thus have therapeutic potential for the treatment of cardiovascular diseases.

• Authors: Takayuki Shindo, Megumu Tanaka, Akiko Kamiyoshi, Yuka Ichikawa-Shindo, Hisaka Kawate, Akihiro Yamauchi, Takayuki Sakurai
• Journal: Peptides (Peptides) Vol. 111 Pg. 55-61 (01 2019) ISSN: 1873-5169 [Electronic] United States
• PMID: 29689347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Receptor Activity-Modifying Protein 2
• Receptor Activity-Modifying Protein 3
• Receptor Activity-Modifying Proteins
• Adrenomedullin

Topics

• Adrenomedullin (metabolism)
• Animals
• Homeostasis (genetics, physiology)
• Mice
• Mice, Knockout
• Receptor Activity-Modifying Protein 2 (genetics, metabolism)
• Receptor Activity-Modifying Protein 3 (genetics, metabolism)
• Receptor Activity-Modifying Proteins (metabolism)