Background Pulmonary hypertension (PH) involves a pulmonary vascular remodeling due to accumulation of α-smooth muscle actin (α-SMA)-expressing mesenchymal-like cells. Aim To demonstrate that endothelial-to-mesenchymal transition (EndoMT) is a source of α-SMA-expressing cells in PH lesions. This process allows endothelial cells (EC) to acquire a mesenchymal/myofibroblastic phenotype. Methods We studied EndoMT in explanted tissue from PH patient and from rat models (sugen-hypoxia SuHx- and monocrotaline MCT-induced PH). Endothelial and subendothelial cells phenotypes were analyzed by multiple staining in immunofluorescence and by electron and correlative microscopy. The loss of endothelial cell-cell junction which is essential for EndoMT was characterized by immunostaining and by Western Blot (WB) (VE-cadherin, p120). We measured the expression of master transcription factors for EndoMT like Twist-1 in both human tissue and PH models. Finally we used rapamycin in MCT-induced PH model to regulate EndoMT. Results Endothelial and mesenchymal markers were expressed in an opposite gradient direction in intimal and plexiform lesions of PAH lung, with a loss of cell-cell junctions between luminal EC. These findings were compatible with an active EndoMT process with transitional EC leaving the luminal layer to constitute the neointima and the core of the plexiform lesions. Moreover, ultrastructural observations and WB quantification supported ongoing EndoMT in PAH. EndoMT was also observed in both rat models and was successfully regulated by rapamycin in the MCT-induced PH. Conclusions EndoMT participates in the vascular remodeling responsible for human and experimental PAH, and this may have therapeutic implications for PH.
Ranchoux et al. (Mon,) studied this question.