The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity

• Published in: The Journal of clinical investigation Vol. 118; no. 1; pp. 29 - 39
• Main Authors: Ichikawa-Shindo, Yuka, Sakurai, Takayuki, Kamiyoshi, Akiko, Kawate, Hisaka, Iinuma, Nobuyoshi, Yoshizawa, Takahiro, Koyama, Teruhide, Fukuchi, Junichi, Iimuro, Satoshi, Moriyama, Nobuo, Kawakami, Hayato, Murata, Toshinori, Kangawa, Kenji, Nagai, Ryozo, Shindo, Takayuki
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.01.2008
• Subjects: Adrenomedullin - genetics; Adrenomedullin - metabolism; Angiogenesis; Animals; Arteries - metabolism; Arteries - pathology; Biomedical research; Calcitonin Receptor-Like Protein; Capillary Permeability - physiology; Cardiovascular diseases; Cardiovascular Diseases - genetics; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - pathology; Cells, Cultured; Edema; Edema - genetics; Edema - metabolism; Edema - pathology; Embryo Loss - genetics; Embryo Loss - metabolism; Embryo Loss - pathology; Embryonic Stem Cells - metabolism; Embryonic Stem Cells - pathology; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Female; Homeostasis; Homeostasis - physiology; Humans; Intracellular Signaling Peptides and Proteins - genetics; Male; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Mice, Knockout; Neovascularization, Physiologic - physiology; Pathogenesis; Peptides; Physiological aspects; Pregnancy; Proteins; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Proteins; Receptors, Adrenomedullin; Receptors, Calcitonin - genetics; Receptors, Calcitonin - metabolism; Receptors, Peptide - genetics; Receptors, Peptide - metabolism; Tight Junctions - genetics; Tight Junctions - metabolism; Tight Junctions - pathology; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci33022

Adrenomedullin (AM) is a peptide involved both in the pathogenesis of cardiovascular diseases and in circulatory homeostasis. The high-affinity AM receptor is composed of receptor activity-modifying protein 2 or 3 (RAMP2 or -3) and the GPCR calcitonin receptor-like receptor. Testing our hypothesis that RAMP2 is a key determinant of the effects of AM on the vasculature, we generated and analyzed mice lacking RAMP2. Similar to AM-/- embryos, RAMP2-/- embryos died in utero at midgestation due to vascular fragility that led to severe edema and hemorrhage. Vascular ECs in RAMP2-/- embryos were severely deformed and detached from the basement membrane. In addition, the abnormally thin arterial walls of these mice had a severe disruption of their typically multilayer structure. Expression of tight junction, adherence junction, and basement membrane molecules by ECs was diminished in RAMP2-/- embryos, leading to paracellular leakage and likely contributing to the severe edema observed. In adult RAMP2+/- mice, reduced RAMP2 expression led to vascular hyperpermeability and impaired neovascularization. Conversely, ECs overexpressing RAMP2 had enhanced capillary formation, firmer tight junctions, and reduced vascular permeability. Our findings in human cells and in mice demonstrate that RAMP2 is a key determinant of the effects of AM on the vasculature and is essential for angiogenesis and vascular integrity.