CD44 and xCT: The Silver Bullet for Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension?
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ABSTRACT:
SUBMITTER: Agrawal V
PROVIDER: S-EPMC6839931 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
| S-EPMC8035923 | biostudies-literature
Project description:Galectin-3 (Gal-3) is highly expressed in fibrotic tissue related to diverse etiologies. endothelial-to-mesenchymal transition (EndoMT), A less well studied phenomenon serves as a critical process in pulmonary vascular remodeling associated with the development of pulmonary arterial hypertension (PAH). EndoMT is hypothesized to contribute to the over-proliferation of αSMA positive cells. We aim to investigate the potential role of Gal-3 in regulating EndoMT in PAH. We observed an upregulation in both Gal-3 and αSMA expression in the monocrotaline (MCT) and Hypoxia PAH model, accompanied with intimal thickening. For more profound vascular remodeling and endothelial layer lesion in former model, we employed Gal-3 knockdown and overexpression lentivirus methodology to the MCT rats to determine the mechanisms underlying abnormal endothelial cell transition in PAH. PAH was evaluated according to right ventricular systolic pressure, right heart hypertrophy and pulmonary artery remodeling. A reduction in Gal-3 was protective against the development of PAH, while Gal-3 upregulation aggravated pulmonary vascular occlusion. In addition, Gal-3 deficiency suppressed pulmonary vascular cell proliferation and macrophage infiltration. Finally, we revealed that in endothelial cells treated with tumor necrosis factor α and hypoxia (representing an in vitro model of PAH), inhibition of Gal-3 by siRNA was able to abolish the associated upregulation of αSMA. These observations suggesting Gal-3 serves as a critical mediator in PAH by regulating EndoMT. Inhibition of Gal-3 may represent a novel therapeutic target for PAH treatment.
| S-EPMC6675525 | biostudies-literature
Project description:Aims:The pathogenic mechanisms of pulmonary arterial hypertension (PAH) remain unclear, but involve dysfunctional endothelial cells (ECs), dysregulated immunity and inflammation in the lung. We hypothesize that a developmental process called endothelial to haematopoietic transition (EHT) contributes to the pathogenesis of pulmonary hypertension (PH). We sought to determine the role of EHT in mouse models of PH, to characterize specific cell types involved in this process, and to identify potential therapeutic targets to prevent disease progression. Methods and results:When transgenic mice with fluorescence protein ZsGreen-labelled ECs were treated with Sugen/hypoxia (Su/Hx) combination to induce PH, the percentage of ZsGreen+ haematopoietic cells in the peripheral blood, primarily of myeloid lineage, significantly increased. This occurrence coincided with the depletion of bone marrow (BM) ZsGreen+ c-kit+ CD45- endothelial progenitor cells (EPCs), which could be detected accumulating in the lung upon PH-induction. Quantitative RT-PCR based gene array analysis showed that key transcription factors driving haematopoiesis were expressed in these EPCs. When transplanted into lethally irradiated recipient mice, the BM-derived EPCs exhibited long-term engraftment and haematopoietic differentiation capability, indicating these EPCs are haemogenic in nature. Specific inhibition of the critical haematopoietic transcription factor Runx1 blocked the EHT process in vivo, prevented egress of the BM EPCs and ultimately attenuated PH progression in Su/Hx- as well as in monocrotaline-induced PH in mice. Thus, myeloid-skewed EHT promotes the development of PH and inhibition of this process prevents disease progression in mouse models of PH. Furthermore, high levels of Runx1 expression were found in circulating CD34+ CD133+ EPCs isolated from peripheral blood of patients with PH, supporting the clinical relevance of our proposed mechanism of EHT. Conclusion:EHT contributes to the pathogenesis of PAH. The transcription factor Runx1 may be a novel therapeutic target for the treatment of PAH.
| S-EPMC5852529 | biostudies-literature
Project description:Oxidative stress and inflammation play key roles in development of pulmonary arterial hypertension (PAH). We previously reported that an endothelial cell (EC)-specific cyclophilin A overexpression mouse developed many characteristics of PAH. In other models of cardiovascular disease, cyclophilin A stimulates smooth muscle proliferation and vascular inflammation, but mechanisms responsible for PAH have not been defined. In particular, the contribution of endothelial-to-mesenchymal transition in cyclophilin A-mediated PAH has not been studied. We identified increased levels of cyclophilin A in endothelial and neointimal cells of pulmonary arteries in patients with PAH and animal pulmonary hypertension models. In the EC-specific cyclophilin A overexpression mouse that exhibited features characteristic of PAH, lineage tracing showed high level expression of mesenchymal markers in pulmonary ECs. A significant number of mesenchymal cells in media and perivascular regions of pulmonary arterioles and alveoli were derived from ECs. Pulmonary ECs isolated from these mice showed phenotypic changes characteristic of endothelial-to-mesenchymal transition in culture. Cultured pulmonary ECs stimulated with extracellular cyclophilin A and acetylated cyclophilin A demonstrated functional changes associated with endothelial-to-mesenchymal transition such as increased cytokine release, migration, proliferation, and mitochondrial dysfunction. Acetylated cyclophilin A stimulated greater increases for most features of endothelial-to-mesenchymal transition. In conclusion, extracellular cyclophilin A (especially acetylated form) contributes to PAH by mechanisms involving increased endothelial-to-mesenchymal transition, cytokine release, EC migration, proliferation, and mitochondrial dysfunction; strengthening the basis for studying cyclophilin A inhibition as a therapy for PAH.
| S-EPMC7485572 | biostudies-literature
Project description:Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. We evaluated the inhibitory effects of nintedanib both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and we evaluated pulmonary hemodynamics and PAs pathology. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.
| S-EPMC6656344 | biostudies-literature
Project description:BackgroundWe previously reported high-throughput RNA sequencing analyses that identified heightened expression of the chromatin architectural factor High Mobility Group AT-hook 1 (HMGA1) in pulmonary arterial endothelial cells (PAECs) from patients who had idiopathic pulmonary arterial hypertension (PAH) in comparison with controls. Because HMGA1 promotes epithelial-to-mesenchymal transition in cancer, we hypothesized that increased HMGA1 could induce transition of PAECs to a smooth muscle (SM)-like mesenchymal phenotype (endothelial-to-mesenchymal transition), explaining both dysregulation of PAEC function and possible cellular contribution to the occlusive remodeling that characterizes advanced idiopathic PAH.Methods and resultsWe documented increased HMGA1 in PAECs cultured from idiopathic PAH versus donor control lungs. Confocal microscopy of lung explants localized the increase in HMGA1 consistently to pulmonary arterial endothelium, and identified many cells double-positive for HMGA1 and SM22α in occlusive and plexogenic lesions. Because decreased expression and function of bone morphogenetic protein receptor 2 (BMPR2) is observed in PAH, we reduced BMPR2 by small interfering RNA in control PAECs and documented an increase in HMGA1 protein. Consistent with transition of PAECs by HMGA1, we detected reduced platelet endothelial cell adhesion molecule 1 (CD31) and increased endothelial-to-mesenchymal transition markers, αSM actin, SM22α, calponin, phospho-vimentin, and Slug. The transition was associated with spindle SM-like morphology, and the increase in αSM actin was largely reversed by joint knockdown of BMPR2 and HMGA1 or Slug. Pulmonary endothelial cells from mice with endothelial cell-specific loss of Bmpr2 showed similar gene and protein changes.ConclusionsIncreased HMGA1 in PAECs resulting from dysfunctional BMPR2 signaling can transition endothelium to SM-like cells associated with PAH.
| S-EPMC4856565 | biostudies-literature
Project description:Pulmonary hypertension (PH) is a fatal disorder characterized by pulmonary vascular remodeling and obstruction. The phosphodiesterase 4 (PDE4) family hydrolyzes cyclic AMP (cAMP) and is comprised of four subtypes (PDE4A-D). Previous studies have shown the beneficial effects of pan-PDE4 inhibitors in rodent PH; however, this class of drugs is associated with side effects owing to the broad inhibition of all four PDE4 isozymes. Here, we demonstrate that PDE4B is the predominant PDE isozyme in lungs and that it was upregulated in rodent and human PH lung tissues. We also confirmed that PDE4B is mainly expressed in the lung endothelial cells (ECs). Evaluation of PH in Pde4b wild type and knockout mice confirmed that Pde4b is important for the vascular remodeling associated with PH. In vivo EC lineage tracing demonstrated that Pde4b induces PH development by driving endothelial-to-mesenchymal transition (EndMT), and mechanistic studies showed that Pde4b regulates EndMT by antagonizing the cAMP-dependent PKA-CREB-BMPRII axis. Finally, treating PH rats with a PDE4B-specific inhibitor validated that PDE4B inhibition has a significant pharmacological effect in the alleviation of PH. Collectively, our findings indicate a critical role for PDE4B in EndMT and PH, prompting further studies of PDE4B-specific inhibitors as a therapeutic strategy for PH.
| S-EPMC10985131 | biostudies-literature
Project description:Bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants, results from mechanical ventilation and hyperoxia, amongst other factors. Although most BPD survivors can be weaned from supplemental oxygen, many show evidence of cardiovascular sequelae in adulthood, including pulmonary hypertension and pulmonary vascular remodeling. Endothelial-mesenchymal transition (EndoMT) plays an important role in mediating vascular remodeling in idiopathic pulmonary arterial hypertension. Whether hyperoxic exposure, a known mediator of BPD in rodent models, causes EndoMT resulting in vascular remodeling and pulmonary hypertension remains unclear. We hypothesized that neonatal hyperoxic exposure causes EndoMT, leading to the development of pulmonary hypertension in adulthood. To test this hypothesis, newborn mice were exposed to hyperoxia and then allowed to recover in room air until adulthood. Neonatal hyperoxic exposure gradually caused pulmonary vascular and right ventricle remodeling as well as pulmonary hypertension. Male mice were more susceptible to developing pulmonary hypertension compared to female mice, when exposed to hyperoxia as newborns. Hyperoxic exposure induced EndoMT in mouse lungs as well as in cultured lung microvascular endothelial cells (LMVECs) isolated from neonatal mice and human fetal donors. This was augmented in cultured LMVECs from male donors compared to those from female donors. Using primary mouse LMVECs, hyperoxic exposure increased phosphorylation of both Smad2 and Smad3, but reduced Smad7 protein levels. Treatment with a selective TGF-β inhibitor SB431542 blocked hyperoxia-induced EndoMT in vitro. Altogether, we show that neonatal hyperoxic exposure caused vascular remodeling and pulmonary hypertension in adulthood. This was associated with increased EndoMT. These novel observations provide mechanisms underlying hyperoxia-induced vascular remodeling and potential approaches to prevent BPD-associated pulmonary hypertension by targeting EndoMT. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
| S-EPMC7927273 | biostudies-literature
Project description:Endothelial‑to‑mesenchymal transition (EndMT) serves an important role in the vascular remodeling of pulmonary arterial hypertension (PAH). However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in PAH and the process of EndMT. Male Sprague‑Dawley rats (10 weeks old) received a single dose of monocrotaline (MCT; i.p., 60 mg/kg) and were randomly treated with NaHS [an H2S donor; intraperitoneal (i.p.) 1 mg/kg/day], DL‑propagylglycine (an inhibitor of H2S synthesis; PAG; i.p., 10 mg/kg/day) or saline, 7 days after MCT injection. Rats were sacrificed 21 days after MCT injection. A selection of human pulmonary artery endothelial cells (HPAECs) were pretreated with NaHS or saline and stimulated with transforming growth factor (TGF)‑β1 (10 ng/ml), and the other HPAECs were transfected with a cystathionine γ‑lyase (CSE, an H2S synthesizing enzyme) plasmid and subsequently stimulated with TGF‑β1. NaHS was indicated to inhibit EndMT and PAH progression by inhibiting the induction of the nuclear factor (NF)‑κB‑Snail pathway. In contrast, the depletion of H2S formation by PAG exacerbated EndMT and PAH by activating NF‑κB‑Snail molecules. In HPAECs, NaHS dose‑dependently inhibited TGF‑β1‑induced EndMT and the activation of the NF‑κB‑Snail pathway. Transfection with a CSE plasmid significantly repressed TGF‑β1‑induced expression of the mesenchymal marker and upregulated the expression of the endothelial marker, which was accompanied by the suppression of the NF‑κB‑Snail pathway. The inhibitory effect of CSE overexpression on TGF‑β1‑induced EndMT was significantly reversed by pretreatment with PAG. In conclusion, the current study provides novel information elucidating the beneficial effect of H2S on PAH through inhibiting the induction of the NF‑κB‑Snail pathway and the subsequent process of EndMT in pulmonary arteries.
| S-EPMC6844600 | biostudies-literature
Project description:Pulmonary arterial hypertension (PAH) is a severe and incurable pulmonary vascular disease. One of the primary origins of PAH is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Our objective was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation. DNA was extracted from cultured PEC from patients with idiopathic PAH (n=11), heritable PAH (n=10) and controls (n=18). ). DNA methylation was assessed using the Illumina HumanMethylation450 Assay. After normalization, samples and probes were clustered according to their methylation profile. Differential clusters were functionally analysed using bioinformatics tools.
2016-07-15 | E-GEOD-84395 | biostudies-arrayexpress