期刊
CIRCULATION
卷 131, 期 11, 页码 1006-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.114.008750
关键词
bone morphogenetic protein receptors, type II; cardiovascular diseases; epithelial-mesenchymal transition; hypertension, pulmonary; models, animal; neointima; sirolimus; TWIST1 protein, human; vascular remodeling; vimentin
资金
- LabEx LERMIT
- Aviesan (ITMO IHP)
- Region Ile de France (CORDDIM)
- National Funding Agency for Research (ANR) [ANR-13-JSV1-001]
- Netherlands Cardiovascular Research Initiative: the Dutch Heart Foundation
- Dutch Federation of University Medical Centers
- Netherlands Organization for Health Research and Development
- Royal Netherlands Academy of Sciences
Background-The vascular remodeling responsible for pulmonary arterial hypertension (PAH) involves predominantly the accumulation of a-smooth muscle actin-expressing mesenchymal-like cells in obstructive pulmonary vascular lesions. Endothelial-to-mesenchymal transition (EndoMT) may be a source of those a-smooth muscle actin-expressing cells. Methods and Results-In situ evidence of EndoMT in human PAH was obtained by using confocal microscopy of multiple fluorescent stainings at the arterial level, and by using transmission electron microscopy and correlative light and electron microscopy at the ultrastructural level. Findings were confirmed by in vitro analyses of human PAH and control cultured pulmonary artery endothelial cells. In addition, the mRNA and protein signature of EndoMT was recognized at the arterial and lung level by quantitative real-time polymerase chain reaction and Western blot analyses. We confirmed our human observations in established animal models of pulmonary hypertension (monocrotaline and SuHx). After establishing the first genetically modified rat model linked to BMPR2 mutations (BMPR2(Delta 140Ex1/+) rats), we demonstrated that EndoMT is linked to alterations in signaling of BMPR2, a gene that is mutated in 70% of cases of familial PAH and in 10% to 40% of cases of idiopathic PAH. We identified molecular actors of this pathological transition, including twist overexpression and vimentin phosphorylation. We demonstrated that rapamycin partially reversed the protein expression patterns of EndoMT, improved experimental PAH, and decreased the migration of human pulmonary artery endothelial cells, providing the proof of concept that EndoMT is druggable. Conclusions-EndoMT is linked to alterations in BPMR2 signaling and is involved in the occlusive vascular remodeling of PAH, findings that may have therapeutic implications.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据