Vascular endothelial-cadherin downregulation as a feature of endothelial transdifferentiation in monocrotaline-induced pulmonary hypertension

Abstract

Increased pulmonary vascular resistance in pulmonary hypertension (PH) is caused by vasoconstriction and obstruction of small pulmonary arteries by proliferating vascular cells. In analogy to cancer, subsets of proliferating cells may be derived from endothelial cells transitioning into a mesenchymal phenotype. To understand phenotypic shifts transpiring within endothelial cells in PH, we injected rats with alkaloid monocrotaline to induce PH and measured lung tissue levels of endothelial-specific protein and critical differentiation marker vascular endothelial (VE)-cadherin. VE-cadherin expression by immonoblotting declined significantly 24 h and 15 days postinjection to rebound to baseline at 30 days. There was a concomitant increase in transcriptional repressors Snail and Slug, along with a reduction in VE-cadherin mRNA. Mesenchymal markers α-smooth muscle actin and vimentin were upregulated by immunohistochemistry and immunoblotting, and α-smooth muscle actin was colocalized with endothelial marker platelet endothelial cell adhesion molecule-1 by confocal microscopy. Apoptosis was limited in this model, especially in the 24-h time point. In addition, monocrotaline resulted in activation of protein kinase B/Akt, endothelial nitric oxide synthase (eNOS), nuclear factor (NF)-κB, and increased lung tissue nitrotyrosine staining. To understand the etiological relationship between nitrosative stress and VE-cadherin suppression, we incubated cultured rat lung endothelial cells with endothelin-1, a vasoconstrictor and pro-proliferative agent in pulmonary arterial hypertension. This resulted in activation of eNOS, NF-κB, and Akt, in addition to induction of Snail, downregulation of VE-cadherin, and synthesis of vimentin. These effects were blocked by eNOS inhibitor N(ω)-nitro-l-arginine methyl ester. We propose that transcriptional repression of VE-cadherin by nitrosative stress is involved in endothelial-mesenchymal transdifferentiation in experimental PH.

Activation of Nrf2 Attenuates Pulmonary Vascular Remodeling via Inhibiting Endothelial-to-Mesenchymal Transition: an Insight from a Plant Polyphenol

“…Recent studies indicate that EndMT is a major cause of pulmonary artery remodeling in MCT-induced PAH in rats 16 . Using double immunofluorescence staining and semi-quantitative analysis, Nikitopoulou et al found that endothelial markers are downregulated and mesenchymal markers are upregulated in MCT-induced pulmonary hypertension 52 . Ghosh et al found that treatment with SB431542, the TGFβ receptor inhibitor, could completely block TGFβ-induced EndMT 53 .…”

Endothelial–Vascular Smooth Muscle Cells Interactions in Atherosclerosis

“…Indeed, transdifferentiation of mature vascular ECs has been detected in pulmonary hypertension, which plays an important role in pulmonary arterial remodeling ( 73 ). This likely happens due to downregulation of EC-cadherin ( 74 ) or regulation by myocardin in hypoxia-induced pulmonary vascular remodeling ( 75 ). However, the causal role of EC-derived VSMC in atherogenesis, if any, remains poorly understood ( 5 ).…”

Glucagon-like peptide-1 (GLP-1) mediates the protective effects of dipeptidyl peptidase IV inhibition on pulmonary hypertension

“…Besides, accumulation of inflammatory cells around pulmonary arteries, including macrophages and mast cells, is another obvious profile of pulmonary vascular remodeling (PRV) [5]. Recently, endothelial-mesenchymal transition (EndMT) has been noted in the pulmonary vascular intima both in patients with PH [6, 7] and in animal model of PH [6, 8]. EndMT results in endothelial dysfunction and pro-inflammatory response [9].…”