Circulation. 2015 Jan 15. pii: CIRCULATIONAHA.114.008750. [Epub ahead of print]
Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension.
Ranchoux B1, Antigny F1, Rucker-Martin C1, Hautefort A1, Péchoux C2, Bogaard HJ3, Dorfmüller P4, Remy S5, Lecerf F1, Planté S6, Chat S2, Fadel E7, Houssaini A8, Anegon I5, Adnot S8, Simonneau G1, Humbert M1, Cohen-Kaminsky S1, Perros F9.

Inserm UMR999, Univ. Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France; Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.

INRA U1196, Jouy-en-Josas, France.

Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

INSERM UMR 1064, Nantes, France.

INSERM U955, Hôpital Henri Mondor, AP-HP, Université Paris-Est Créteil (UPEC), Créteil, France.

Abstract

BACKGROUND: The vascular remodeling responsible for pulmonary arterial hypertension (PAH) involves predominantly accumulation of α-smooth muscle actin (α-SMA)-expressing mesenchymal-like cells in obstructive pulmonary vascular lesions. Endothelial-to-mesenchymal transition (EndoMT) may be a source of those α-SMA-expressing cells.
METHODS AND RESULTS: In situ evidence of EndoMT in human PAH was obtained, using confocal microscopy of multiple fluorescent stainings at the arterial level, and using transmission electron microscopy (TEM) and correlative light and electron microscopy (CLEM) at the ultrastructural level. Findings were confirmed by in vitro analyses of human PAH and control cultured pulmonary artery endothelial cells (PAEC). In addition, the mRNA and protein signature of EndoMT was recognized at the arterial and lung level by quantitative RT-PCR and Western blot analyses. We confirmed our human observations in established animal models of pulmonary hypertension (MCT and SuHx). After establishing the first genetically modified rat model linked to BMPR2 mutations (BMPR2Δ140Ex1/+ 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 10-40 % 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 PAEC, 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, which findings may have therapeutic implications.

KEYWORDS:
BMPR2; Rapamycin; Twist-1; Vimentin; animal model cardiovascular disease; endothelial-to-mesenchymal transition; intima-media thickness; neointima; pulmonary hypertension; pulmonary vascular changes

PMID: 25593290