The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity.
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.
Ichikawa-Shindo
Yuka
Y
Department of Organ Regeneration, Shinshu University Graduate School of Medicine, Nagano, Japan.
Sakurai
Takayuki
T
Kamiyoshi
Akiko
A
Kawate
Hisaka
H
Iinuma
Nobuyoshi
N
Yoshizawa
Takahiro
T
Koyama
Teruhide
T
Fukuchi
Junichi
J
Iimuro
Satoshi
S
Moriyama
Nobuo
N
Kawakami
Hayato
H
Murata
Toshinori
T
Kangawa
Kenji
K
Nagai
Ryozo
R
Shindo
Takayuki
T
D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D058286:Calcitonin Receptor-Like Protein; D002199:Capillary Permeability / Q000502:physiology*; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004487:Edema / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020964:Embryo Loss / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011247:Pregnancy; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism / Q000473:pathology
C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; C545579:Calcrl protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C545503:RAMP2 protein, human; C545506:Ramp2 protein, mouse; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin; D018000:Receptors, Peptide; D053607:Adrenomedullin