Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension.
Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension.
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DOI：
10.1161/circulationaha.107.736801
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发表时间：
2008-08-12
期刊：
影响因子：
37.8
通讯作者：
Oh SP
中科院分区：
文献类型：
--
作者：
Hong KH;Lee YJ;Lee E;Park SO;Han C;Beppu H;Li E;Raizada MK;Bloch KD;Oh SP
肺动脉高压（PAH）是一种罕见但致命的肺部疾病，病因多样。PAH现在进一步细分为特发性（IPAH），家族性（FPAH）和相关（APAH）品种。在50-70%的FPAH患者和10-40%的IPAH患者中可以检测到BMPR 2的杂合突变。尽管内皮细胞被怀疑是PAH发病机制的细胞来源，但没有明确的体内直接证据。本研究旨在研究内皮细胞Bmpr 2缺失是否会导致PAH。使用Bmpr 2条件性敲除小鼠和一种新的内皮Cre转基因小鼠系在肺内皮细胞（佩奇）中缺失Bmpr 2基因。与对照小鼠（19.9 - 26.7 mmHg，中位数：23 mmHg）相比，在2 - 7月龄时，在佩奇中Bmpr 2条件性缺失的杂合（21.7 - 44.1 mmHg，中位数：23.7 mmHg）和纯合（20.7- 56.3 mmHg，中位数：27 mmHg）小鼠中观察到宽范围的右心室收缩压（RVSP）。RVSP大于30 mmHg的小鼠亚组表现出右心室肥大和肌化远端肺动脉的数量和壁厚增加。在这些高RVSP小鼠的肺中，参与PAH发病机制的蛋白质（如5-羟色胺转运体和腱生蛋白-C）的表达在远端动脉中升高，血管周围白细胞浸润和原位血栓形成的发生率较高。佩奇中条件性杂合或纯合Bmpr 2缺失使小鼠易于发生PAH。
Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease of diverse etiologies. PAH is now further subclassified as idiopathic (IPAH), familial (FPAH) and associated (APAH) varieties. Heterozygous mutations in BMPR2 can be detected in 50-70% of patients with FPAH and 10-40% of patients with IPAH. Although endothelial cells have been suspected as the cellular origin of PAH pathogenesis, no direct in vivo evidence has been clearly presented. The present study was designed to investigate whether endothelial Bmpr2 deletion can predispose to PAH. The Bmpr2 gene was deleted in pulmonary endothelial cells (pECs) using Bmpr2 conditional knockout mice and a novel endothelial Cre transgenic mouse line. Wide ranges of right ventricular systolic pressure (RVSP) were observed in mice with heterozygous (21.7 - 44.1 mmHg, median: 23.7 mmHg) and homozygous (20.7- 56.3 mmHg, median: 27 mmHg) conditional deletion of Bmpr2 in pECs in comparison with control mice (19.9 - 26.7 mmHg, median: 23 mmHg) at two to seven months of age. A subset of mice with RVSP greater than 30 mmHg exhibited right ventricular hypertrophy and an increase in the number and wall thickness of muscularized distal pulmonary arteries. In the lungs of these high RVSP mice, expression of proteins involved in the pathogenesis of PAH, such as serotonin transporter and tenacin-C, were elevated in distal arteries, and had a high incidence of perivascular leukocyte infiltration and in situ thrombosis. Conditional hetero or homozygous Bmpr2 deletion in pECs predisposes mice to develop PAH.