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
Department of Organ Regeneration, Shinshu University Graduate School of Medicine, Nagano, Japan.
J Clin Invest. 2008 Jan;118(1):29-39. 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.
肾上腺髓质素(AM)是一种参与心血管疾病发病机制和循环稳态的肽。高亲和力AM受体由受体活性修饰蛋白2或3(RAMP2或-3)和G蛋白偶联受体(GPCR)降钙素受体样受体组成。为了验证我们的假设,即RAMP2是AM对血管系统作用的关键决定因素,我们构建并分析了缺乏RAMP2的小鼠。与AM基因敲除胚胎相似,RAMP2基因敲除胚胎在妊娠中期死于子宫内,原因是血管脆性导致严重水肿和出血。RAMP2基因敲除胚胎中的血管内皮细胞严重变形并与基底膜分离。此外,这些小鼠异常薄的动脉壁严重破坏了其典型的多层结构。RAMP2基因敲除胚胎中内皮细胞紧密连接、黏附连接和基底膜分子的表达减少,导致细胞旁渗漏,并可能导致观察到的严重水肿。在成年RAMP2杂合子小鼠中,RAMP2表达降低导致血管通透性增加和新生血管形成受损。相反,过表达RAMP2的内皮细胞具有增强的毛细血管形成、更紧密的紧密连接和降低的血管通透性。我们在人类细胞和小鼠中的研究结果表明,RAMP2是AM对血管系统作用的关键决定因素,对血管生成和血管完整性至关重要。