Endothelial-to-mesenchymal transition: Pathogenesis and therapeutic targets for chronic pulmonary and vascular diseases

Lu, Xin; Gong, Jiannan; Dennery, Phyllis A.; Yao, Hongwei

doi:10.1016/j.bcp.2019.06.021

Cited by 32 publications

(23 citation statements)

References 99 publications

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“…The TGF‐β/Smad pathway is a critical signal for triggering EndoMT. This is characterized by increased phosphorylation of Smad2 and Smad3 [20]. Therefore, we first measured the phosphorylation of Smad2 (Ser465/467) and Smad3 (Ser423/425) in mouse LMVECs exposed to hyperoxia followed by air recovery.…”

Section: Resultsmentioning

confidence: 99%

“…Primary LMVECs were isolated from neonatal mice (3–5 days old) and characterized as described previously [20]. These cells were cultured in dishes/plates pre‐coated with 30 μg/ml human fibronectin using VascuLife® EnGS‐Mv medium, which was changed every 24 h. Primary LMVECs at passages 3–5 were used for experiments.…”

Section: Methodsmentioning

confidence: 99%

“…Similarly, we also isolated LMVECs from hyperoxia‐exposed mice for measuring Vim and Acta2 gene expression. Mouse fetal lung EC lines (MFLM‐91U cells) were purchased from Seven Hills Bioreagents (Cincinnati, OH, USA), and grown in UltraCulture medium (BioWhittaker) [20]. We verified that there was no mycoplasma contamination.…”

Section: Methodsmentioning

confidence: 99%

“…Cells at 70–80% confluence were exposed to hyperoxia (95% O 2 and 5% CO 2 ) or air (21% O 2 and 5% CO 2 ) for 24 h, followed by normoxia (21% O 2 and 5% CO 2 ) for 24 h [20]. Culture media were changed every 24 h. Newborn C57BL/6J mice (< 12 h old) along with their mothers were exposed to room air or hyperoxia (>95% O 2 ) for 72 h in an A‐chamber (BioSpherix, Parish, NY, USA) [20]. The dams were switched every 24 h between room air and hyperoxia to avoid injury.…”

Section: Methodsmentioning

confidence: 99%

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Endothelial to mesenchymal transition during neonatal hyperoxia‐induced pulmonary hypertension

Gong

Feng

Peterson

et al. 2020

The Journal of Pathology

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Endothelial to mesenchymal transition during neonatal hyperoxia‐induced pulmonary hypertension

Gong

Feng

Peterson

et al. 2020

The Journal of Pathology

Self Cite

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“…KMT2C knockdown has been shown to promote EMT, while forced expression of KMT2C decreased the expression of EMT-related proteins [67]. EMT is considered an important mechanism underlying neonatal respiratory disease [45,68,69]. Thus, peptides derived from the KMT2C protein ( 746 EGCVK 750 and 3890 QQNNLSNP 3897 ) may influence neonatal respiratory diseases.…”

Section: Discussionmentioning

confidence: 99%

Peptidome Analysis of Umbilical Cord Mesenchymal Stem Cell (hUC-MSC) Conditioned Medium from Preterm and Term Infants

Wang

Zhang

et al. 2020

Preprint

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Background : The therapeutic role of mesenchymal stem cells (MSCs) has been widely confirmed in several animal models of premature infant diseases. Micromolecule peptides have shown promise for the treatment of premature infant diseases. However, the potential role of peptides secreted from MSCs has not been studied. The purpose of this study is to broaden the knowledge of the hUC-MSC secretome at the peptide level through peptidomic profile analysis. Methods : We used tandem mass tag (TMT) labeling technology followed by tandem mass spectrometry to compare the peptidomic profile of preterm and term umbilical cord MSC (hUC-MSC) conditioned medium (CM). Gene Ontology (GO) enrichment analysis and Ingenuity Pathway Analysis (IPA) were conducted to explore the differentially expressed peptides by predicting the functions of their precursor proteins. And we investigated the effects of differentially expressed peptides on human lung epithelial cells stimulated by hydrogen peroxide (H 2 O 2 ). Results : A total of 131 peptides derived from 106 precursor proteins were differentially expressed in the preterm hUC-MSC CM compared with the term group, comprising 37 up-regulated peptides and 94 down-regulated peptides. Bioinformatics analysis showed that these differentially expressed peptides may be associated with developmental disorders, inflammatory response and organismal injury. We also found that two differentially expressed peptides reduced the levels of TNFα and IL 1β mRNA in H 2 O 2 -treated human lung epithelial cells. Conclusions : In summary, this study provides further secretomics information on hUC-MSCs and provides a series of peptides that might have roles in premature infant diseases, which may be helpful for prevention and treatment.

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Single‐Cell Transcriptomic Census of Endothelial Changes Induced by Matrix Stiffness and the Association with Atherosclerosis

Zamani

Cheng

Charbonier

et al. 2022

Adv Funct Materials

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Vascular endothelial cell (EC) plasticity plays a critical role in the progression of atherosclerosis by giving rise to mesenchymal phenotypes in the plaque lesion. Despite the evidence for arterial stiffening as a major contributor to atherosclerosis, the complex interplay among atherogenic stimuli in vivo has hindered attempts to determine the effects of extracellular matrix (ECM) stiffness on endothelial‐mesenchymal transition (EndMT). To study the regulatory effects of ECM stiffness on EndMT, an in vitro model is developed in which human coronary artery ECs are cultured on physiological or pathological stiffness substrates. Leveraging single‐cell RNA sequencing, cell clusters with mesenchymal transcriptional features are identified to be more prevalent on pathological substrates than physiological substrates. Trajectory inference analyses reveal a novel mesenchymal‐to‐endothelial reverse transition, which is blocked by pathological stiffness substrates, in addition to the expected EndMT trajectory. ECs pushed to a mesenchymal character by pathological stiffness substrates are enriched in transcriptional signatures of atherosclerotic ECs from human and murine plaques. This study characterizes at single‐cell resolution the transcriptional programs that underpin EC plasticity in both physiological or pathological milieus, and thus serves as a valuable resource for more precisely defining EndMT and the transcriptional programs contributing to atherosclerosis.

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Endothelial-to-mesenchymal transition: Pathogenesis and therapeutic targets for chronic pulmonary and vascular diseases

Cited by 32 publications

References 99 publications

Endothelial to mesenchymal transition during neonatal hyperoxia‐induced pulmonary hypertension

Endothelial to mesenchymal transition during neonatal hyperoxia‐induced pulmonary hypertension

Peptidome Analysis of Umbilical Cord Mesenchymal Stem Cell (hUC-MSC) Conditioned Medium from Preterm and Term Infants

Single‐Cell Transcriptomic Census of Endothelial Changes Induced by Matrix Stiffness and the Association with Atherosclerosis

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