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The GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity
Yuka Ichikawa-Shindo, … , Ryozo Nagai, Takayuki Shindo
Yuka Ichikawa-Shindo, … , Ryozo Nagai, Takayuki Shindo
Published December 20, 2007
Citation Information: J Clin Invest. 2008;118(1):29-39. https://doi.org/10.1172/JCI33022.
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Research Article Article has an altmetric score of 3

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

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Abstract

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.

Authors

Yuka Ichikawa-Shindo, Takayuki Sakurai, Akiko Kamiyoshi, Hisaka Kawate, Nobuyoshi Iinuma, Takahiro Yoshizawa, Teruhide Koyama, Junichi Fukuchi, Satoshi Iimuro, Nobuo Moriyama, Hayato Kawakami, Toshinori Murata, Kenji Kangawa, Ryozo Nagai, Takayuki Shindo

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Figure 1

RAMP2 expression during development and generation of RAMP2 knockout mice.

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RAMP2 expression during development and generation of RAMP2 knockout mic...
(A) Real-time PCR analysis of gene expression during E11.5–E14.5 in WT embryos. Expression is shown relative to that at E11.5. n = 5 per time point. AM, CRLR and RAMPs were expressed during midgestation. (B) In situ hybridization of RAMP2 in WT embryos. Sections of umbilical artery, aortic arch, and lung from E12.5 WT embryos were used. Intense RAMP2 expression was detected in the vascular ECs. Scale bars: 20 μm. (C) Targeted disruption of mouse RAMP2. The genomic locus and predicted targeted locus are shown. Boxes denote exons 1–4 of RAMP2; ScaI and NheI restriction sites and loxP sites are indicated. Probes for Southern blot analysis are shown. (D–F) Southern blot analysis of mouse genomic DNA. (D) DNA was digested with NheI and probed with the 5′ probe. The 7.9-kb and 18.3-kb fragments denote floxed and WT alleles, respectively. (E) DNA was digested with ScaI and probed with the Neo probe. The 8.1-kb fragment denotes flox. (F) DNA was digested with ScaI and probed with the 3′ probe. The 8.1-kb ScaI fragment denotes flox; the 12.4-kb fragment denotes WT. The 4.9-kb fragment denotes the KO allele, generated by deletion of the loxP site using Cre recombinase.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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