Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension

Abstract

Endothelial-to-mesenchymal transition (EndMT) is a process that encompasses extensive transcriptional reprogramming of activated endothelial cells leading to a shift toward mesenchymal cellular phenotypes and functional responses. Initially observed in the context of embryonic development, in the last few decades EndMT is increasingly recognized as a process that contributes to a variety of pathologies in the adult organism. Within the settings of cardiovascular biology, EndMT plays a role in various diseases, including atherosclerosis, heart valvular disease, cardiac fibrosis, and myocardial infarction. EndMT is also being progressively implicated in development and progression of pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH). This review covers the current knowledge about EndMT in PH and PAH, and provides comprehensive overview of seminal discoveries. Topics covered include evidence linking EndMT to factors associated with PAH development, including hypoxia responses, inflammation, dysregulation of bone-morphogenetic protein receptor 2 (BMPR2), and redox signaling. This review amalgamates these discoveries into potential insights for the identification of underlying mechanisms driving EndMT in PH and PAH, and discusses future directions for EndMT-based therapeutic strategies in disease management. Antioxid. Redox Signal. 34, 891-914.

Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension

“…The increase in calpain-1/2 associated with Piezo1-driven Ca 2 þ influx may also contribute to the development of pulmonary vascular remodeling by inducing extracellular matrix remodeling, vascular fibrosis, and arterial calcification (47,49,50,88). Calpain may also activate TGF-b1 and AKT/mTORC2 signaling (50) and induce EndMT in PAECs (89)(90)(91).…”

“…The Jag-mediated Notch activation in PASMCs can also result in small arterial wall thickening and arteriole muscularization by stimulating PASMC proliferation and recruitment (61,82,125). The ECs with upregulated Jag-1/2/3 can also interact with adjacent ECs to induce EndMT by activating endothelial Notch receptors (126-128) and, potentially, cause occlusive intimal lesions (83,89,91,122,129,130). Stretch-mediated opening of upregulated Piezo1 channels in PAECs may lead to Ca 2 þ -dependent SNAI1 expression (131) causing EndMT and to Ca 2 þ -dependent growth factor (e.g., PDGF) synthesis (132,133) causing arteriole muscularization via a paracrine mechanism (134)(135)(136).…”

Endothelial to Mesenchymal Transition in Pulmonary Vascular Diseases

“…Growing evidence suggests that EndMT potentially contributes to endothelial dysfunction and the vascular remodeling of PAH [ 7 , 11 , 22 , 23 ]. Indeed, many studies have demonstrated that various signaling pathways and mediators, including transforming growth factor beta (TGFβ), nuclear factor kappa B (NF-κB), Notch, and microRNA, are involved in the EndMT of PAH [ 24 , 25 ]. It has been reported that the endothelial-specific loss of BMPR2, known as the principal mutation factor of heritable PAH, induces EndMT in vitro and in vivo [ 7 , 11 , 23 ].…”

Endothelial CFTR dysfunction and its involvement in the pathogenesis of pulmonary arterial hypertension

“…EndMT is a process whereby ECs lose their key endothelial traits and start expressing mesenchymal markers. As such, EndMT may directly or indirectly contribute to PAH, by EC transformation into smooth muscle-like cells with higher proliferative and migratory potential [10]. Accordingly, we recently underlined that various CFTR-impaired EC models showed limited EndMT, which might represent a secondary event due to CFTR-related endothelial dysfunction (figure 1).…”

“…Histologically, PAH is characterised by the muscularisation of arterioles, intimal fibrosis and medial hypertrophy, and the hyperproliferation of ECs and vSMCs, as was found from CFTR-impaired models (figure 1) [2]. Multiple studies have also characterised endothelial-to-mesenchymal transition (EndMT) to be involved in the vascular remodelling in PAH [10]. EndMT is a process whereby ECs lose their key endothelial traits and start expressing mesenchymal markers.…”