scholarly journals Regulation of Partial and Reversible Endothelial-to-Mesenchymal Transition in Angiogenesis

2021 ◽  
Vol 9 ◽  
Author(s):  
Jennifer S. Fang ◽  
Nan W. Hultgren ◽  
Christopher C. W. Hughes
Keyword(s):  
Endothelial Cells ◽  
Mesenchymal Cells ◽  
Regulatory Mechanisms ◽  
Mesenchymal Transition ◽  
Pathological Angiogenesis ◽  
Endothelial To Mesenchymal Transition

During development and in several diseases, endothelial cells (EC) can undergo complete endothelial-to-mesenchymal transition (EndoMT or EndMT) to generate endothelial-derived mesenchymal cells. Emerging evidence suggests that ECs can also undergo a partial EndoMT to generate cells with intermediate endothelial- and mesenchymal-character. This partial EndoMT event is transient, reversible, and supports both developmental and pathological angiogenesis. Here, we discuss possible regulatory mechanisms that may control the EndoMT program to dictate whether cells undergo complete or partial mesenchymal transition, and we further consider how these pathways might be targeted therapeutically in cancer.

scholarly journals Epithelial Wntless (Wls) regulates postnatal alveologenesis

Development ◽  
2021 ◽  
Author(s):  
Yinshan Fang ◽  
Hongxia Shao ◽  
Qi Wu ◽  
Neng Chun Wong ◽  
Natalie Tsong ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Gas Exchange ◽  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Alveolar Epithelium ◽  
Mesenchymal Cells ◽  
Collagen Deposition ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition ◽  
Alveolar Formation

Alveologenesis requires the coordinated modulation of the epithelial and mesenchymal compartments to generate mature alveolar saccules for efficient gas exchange. However, the molecular mechanisms underlying the epithelial-mesenchymal interaction during alveologenesis are poorly understood. Here, we report that Wnts produced by epithelial cells are critical for neonatal alveologenesis. Deletion of the Wnt chaperon protein Wntless homolog (Wls) disrupts alveolar formation, resulting in enlarged saccules in Sftpc-Cre/Nkx2.1-Cre; Wlsloxp/loxp mutants. Although commitment of the alveolar epithelium is unaffected, α-SMA+ mesenchymal cells persist in the alveoli accompanied by increased collagen deposition and mutants exhibit exacerbated fibrosis following bleomycin challenge. Notably, α-SMA+ cells include a significant number of endothelial cells resembling endothelial to mesenchymal transition (EndMT) which is also present in Ager-CreER; Wlsloxp/loxp mutants following early postnatal Wls deletion. These findings provide initial evidence that epithelial-derived Wnts are critical for the differentiation of the surrounding mesenchyme during early postnatal alveologenesis.

scholarly journals Isolation and characterization of endothelial-to-mesenchymal transition cells in pulmonary arterial hypertension

2018 ◽  
Vol 314 (1) ◽  
pp. L118-L126 ◽  
Author(s):  
Toshio Suzuki ◽  
Erica J. Carrier ◽  
Megha H. Talati ◽  
Anandharajan Rathinasabapathy ◽  
Xinping Chen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Conditioned Medium ◽  
Mesenchymal Cells ◽  
Paracrine Effects ◽  
Mesenchymal Transition ◽  
Pulmonary Arterial ◽  
Endothelial To Mesenchymal Transition

Endothelial-to-mesenchymal transition (EndMT) is a process in which endothelial cells lose polarity and cell-to cell contacts, and undergo a dramatic remodeling of the cytoskeleton. It has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). However, the characteristics of cells which have undergone EndMT cells in vivo have not been reported and so remain unclear. To study this, sugen5416 and hypoxia (SuHx)-induced PAH was established in Cdh5-Cre/Gt(ROSA)26Sortm4(ACTB-tdTomato,EGFP)Luo/J double transgenic mice, in which GFP was stably expressed in pan-endothelial cells. After 3 wk of SuHx, flow cytometry and immunohistochemistry demonstrated CD144-negative and GFP-positive cells (complete EndMT cells) possessed higher proliferative and migratory activity compared with other mesenchymal cells. While CD144-positive and α-smooth muscle actin (α-SMA)-positive cells (partial EndMT cells) continued to express endothelial progenitor cell markers, complete EndMT cells were Sca-1-rich mesenchymal cells with high proliferative and migratory ability. When transferred in fibronectin-coated chamber slides containing smooth muscle media, α-SMA robustly expressed in these cells compared with cEndMT cells that were grown in maintenance media. Demonstrating additional paracrine effects, conditioned medium from isolated complete EndMT cells induced enhanced mesenchymal proliferation and migration and increased angiogenesis compared with conditioned medium from resident mesenchymal cells. Overall, these findings show that EndMT cells could contribute to the pathogenesis of PAH both directly, by transformation into smooth muscle-like cells with higher proliferative and migratory potency, and indirectly, through paracrine effects on vascular intimal and medial proliferation.

scholarly journals Endothelial-Mesenchymal Transition in Cardiovascular Disease

2021 ◽  
Author(s):  
Zahra Alvandi ◽  
Joyce Bischoff
Keyword(s):  
Endothelial Cells ◽  
Transforming Growth Factor ◽  
Mesenchymal Cell ◽  
Mesenchymal Cells ◽  
Cellular Migration ◽  
Cell Junctions ◽  
Phenotypic Modulation ◽  
Mesenchymal Transition ◽  
Endothelial Junctions ◽  
Endothelial To Mesenchymal Transition

Endothelial-to-mesenchymal transition is a dynamic process in which endothelial cells suppress constituent endothelial properties and take on mesenchymal cell behaviors. To begin the process, endothelial cells loosen their cell-cell junctions, degrade the basement membrane, and migrate out into the perivascular surroundings. These initial endothelial behaviors reflect a transient modulation of cellular phenotype, that is, a phenotypic modulation, that is sometimes referred to as partial endothelial-to-mesenchymal transition. Loosening of endothelial junctions and migration are also seen in inflammatory and angiogenic settings such that endothelial cells initiating endothelial-to-mesenchymal transition have overlapping behaviors and gene expression with endothelial cells responding to inflammatory signals or sprouting to form new blood vessels. Reduced endothelial junctions increase permeability, which facilitates leukocyte trafficking, whereas endothelial migration precedes angiogenic sprouting and neovascularization; both endothelial barriers and quiescence are restored as inflammatory and angiogenic stimuli subside. Complete endothelial-to-mesenchymal transition proceeds beyond phenotypic modulation such that mesenchymal characteristics become prominent and endothelial functions diminish. In proadaptive, regenerative settings the new mesenchymal cells produce extracellular matrix and contribute to tissue integrity whereas in maladaptive, pathologic settings the new mesenchymal cells become fibrotic, overproducing matrix to cause tissue stiffness, which eventually impacts function. Here we will review what is known about how TGF (transforming growth factor) β influences this continuum from junctional loosening to cellular migration and its relevance to cardiovascular diseases.

scholarly journals Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype

2016 ◽  
Vol 310 (11) ◽  
pp. L1185-L1198 ◽  
Author(s):  
Toshio Suzuki ◽  
Yuji Tada ◽  
Rintaro Nishimura ◽  
Takeshi Kawasaki ◽  
Ayumi Sekine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Vascular Endothelial Cells ◽  
Repair Process ◽  
Vascular Endothelial ◽  
Mesenchymal Transition ◽  
Oxidase Inhibition ◽  
Endothelial To Mesenchymal Transition

Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c- kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.

scholarly journals LncRNA AERRIE Is Required for Sulfatase 1 Expression, but Not for Endothelial-to-Mesenchymal Transition

2021 ◽  
Vol 22 (15) ◽  
pp. 8088
Author(s):  
Tan Phát Pham ◽  
Anke S. van Bergen ◽  
Veerle Kremer ◽  
Simone F. Glaser ◽  
Stefanie Dimmeler ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Transcription Factors ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Inflammatory Signals ◽  
Pathological Conditions ◽  
Non Coding Rna ◽  
Endothelial To Mesenchymal Transition ◽  
Long Non Coding Rna

Endothelial cells can acquire a mesenchymal phenotype through a process called Endothelial-to-Mesenchymal transition (EndMT). This event is found in embryonic development, but also in pathological conditions. Blood vessels lose their ability to maintain vascular homeostasis and ultimately develop atherosclerosis, pulmonary hypertension, or fibrosis. An increase in inflammatory signals causes an upregulation of EndMT transcription factors, mesenchymal markers, and a decrease in endothelial markers. In our study, we show that the induction of EndMT results in an increase in long non-coding RNA AERRIE expression. JMJD2B, a known EndMT regulator, induces AERRIE and subsequently SULF1. Silencing of AERRIE shows a partial regulation of SULF1 but showed no effect on the endothelial and mesenchymal markers. Additionally, the overexpression of AERRIE results in no significant changes in EndMT markers, suggesting that AERRIE is marginally regulating mesenchymal markers and transcription factors. This study identifies AERRIE as a novel factor in EndMT, but its mechanism of action still needs to be elucidated.

scholarly journals Endothelial Cells Tissue-Specific Origins Affects Their Responsiveness to TGF-β2 during Endothelial-to-Mesenchymal Transition

2019 ◽  
Vol 20 (3) ◽  
pp. 458 ◽  
Author(s):  
Fernanda Ursoli Ferreira ◽  
Lucas Eduardo Botelho Souza ◽  
Carolina Hassibe Thomé ◽  
Mariana Tomazini Pinto ◽  
Clarice Origassa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Umbilical Vein ◽  
Transforming Growth Factor Β ◽  
Selective Inhibition ◽  
Mesenchymal Transition ◽  
Best Response ◽  
Endothelial To Mesenchymal Transition

The endothelial-to-mesenchymal transition (EndMT) is a biological process where endothelial cells (ECs) acquire a fibroblastic phenotype after concomitant loss of the apical-basal polarity and intercellular junction proteins. This process is critical to embryonic development and is involved in diseases such as fibrosis and tumor progression. The signaling pathway of the transforming growth factor β (TGF-β) is an important molecular route responsible for EndMT activation. However, it is unclear whether the anatomic location of endothelial cells influences the activation of molecular pathways responsible for EndMT induction. Our study investigated the molecular mechanisms and signaling pathways involved in EndMT induced by TGF-β2 in macrovascular ECs obtained from different sources. For this purpose, we used four types of endothelial cells (coronary artery endothelial cells, CAECs; primary aortic endothelial cells PAECs; human umbilical vein endothelia cells, HUVECs; and human pulmonary artery endothelial cells, HPAECs) and stimulated with 10 ng/mL of TGF-β2. We observed that among the ECs analyzed in this study, PAECs showed the best response to the TGF-β2 treatment, displaying phenotypic changes such as loss of endothelial marker and acquisition of mesenchymal markers, which are consistent with the EndMT activation. Moreover, the PAECs phenotypic transition was probably triggered by the extracellular signal–regulated kinases 1/2 (ERK1/2) signaling pathway activation. Therefore, the anatomical origin of ECs influences their ability to undergo EndMT and the selective inhibition of the ERK pathway may suppress or reverse the progression of diseases caused or aggravated by the involvement EndMT activation.

Mesenchymal stem cells alleviate palmitic acid-induced endothelial-to-mesenchymal transition by suppressing endoplasmic reticulum stress

2020 ◽  
Vol 319 (6) ◽  
pp. E961-E980
Author(s):  
Ruixi Luo ◽  
Linzhao Li ◽  
Xiaohong Liu ◽  
Yujia Yuan ◽  
Wuzheng Zhu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Mesenchymal Stem Cells ◽  
Endothelial Dysfunction ◽  
Palmitic Acid ◽  
Er Stress ◽  
Critical Role ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

High levels of plasma free fatty acids (FFAs) lead to endothelial dysfunction (ED), which is involved in the pathogenesis of metabolic syndrome, diabetes, and atherosclerosis. Endoplasmic reticulum (ER) stress and endothelial-to-mesenchymal transition (EndMT) are demonstrated to be mechanistically related to endothelial dysfunction. Mesenchymal stem cells (MSCs) have exhibited an extraordinary cytoprotective effect on cellular lipotoxicity and vasculopathy. However, the underlying mechanisms have not been clearly defined. In the present study, we investigated whether MSCs could ameliorate palmitic acid (PA)-induced endothelial lipotoxicity by reducing ER stress and EndMT. We observed that MSC cocultures substantially alleviated PA-induced lipotoxicity in human umbilical vein endothelial cells (HUVECs). MSCs were able to restore the cell viability, increase tubule formation and migration ability, and decrease inflammation response and lipid deposition. Furthermore, PA caused endothelial-to-mesenchymal transition in HUVECs, which was abrogated by MSCs possibly through inhibiting ER stress. In addition, PA stimulated MSCs to secrete more stanniocalcin-1 (STC-1). Knocking down of STC-1 in MSCs attenuated their effects on PA-induced lipotoxicity in HUVECs. In vivo, MSC transplantation alleviated dyslipidemia and endothelial dysfunction in high-fat diet-fed Sprague–Dawley rats. MSC-treated rats showed reduced expressions of ER stress-related genes in aortas and suppressed expressions of EndMT-related proteins in rat aortic endothelial cells. Overall, our findings indicated that MSCs were able to attenuate endothelial lipotoxicity through inhibiting ER stress and EndMT, in which STC-1 secreted from MSCs may play a critical role.

Sign in / Sign up

Export Citation Format

Share Document