SNAI1, an endothelial–mesenchymal transition transcription factor, promotes the early phase of ocular neovascularization

Sun, Jiaxing; Chang, Tianfang; Li, Manhong; Sun, Lu; Yan, Xianchun; Yang, Ziyan; Liu, Yuan; Xu, W.; Lv, Yang; Su, Jingbo; Liang, Liang; Han, Hua; Dou, Guo‐Rui; Wang, Yusheng

doi:10.1007/s10456-018-9614-9

Cited by 37 publications

(26 citation statements)

References 48 publications

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“…Snai1 is also prominently described for its key role in angiogenesis. Snai1 is expressed on sprouting vessels under both physiological conditions in the developing retinal vasculature and in pathological angiogenic models of laser photocoagulation-induced CNV and oxygen-induced retinopathy (OIR) mouse models [5]. Snai1 overexpression in human umbilical vascular endothelial cells (HUVECs) induced cellular elongation and enhanced cell motility with lamellipodia formation, whereas Snai1 knockdown blocked migration, invasion and sprouting.…”

Section: Evidence and Molecular Drivers Of Emt/endmt In Amdmentioning

confidence: 99%

“…In the context of AMD, retinal pigment epithelial (RPE) cells lose their cell-cell adhesions and apical-basal polarity, transforming into mesenchymal cells through EMT [4]. Another emerging hypothesis is the role of endothelial-mesenchymal transition (EndMT) in contributing to the mesenchymal cell population [5]. In neovascular AMD (nAMD), angiogenesis initiates inflammatory cell recruitment and increases oxygen supply and nutrients to the macular region [6].…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, the process of EMT in RPE is not limited to subretinal fibrosis in AMD but rather, has also been extensively studied and described in the context of proliferative vitreoretinopathy (PVR) [7], epiretinal membrane (ERM) [8], and retinal fibrosis in proliferative diabetic retinopathy (PDR) [9]. Similarly, EndMT has been studied in both choroidal and retinal endothelial cells in numerous ocular angiogenic diseases in addition to nAMD, including proliferative diabetic retinopathy and retinopathy of prematurity (ROP) [5,10]. Hence, mechanistic insights in EMT and EndMT gleaned from studies outside of AMD may help to guide future AMD research.…”

Section: Introductionmentioning

confidence: 99%

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EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

Shu

Butcher

Saint‐Geniez

2020

IJMS

151

117

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Epithelial–mesenchymal transition (EMT) and endothelial–mesenchymal transition (EndMT) are physiological processes required for normal embryogenesis. However, these processes can be hijacked in pathological conditions to facilitate tissue fibrosis and cancer metastasis. In the eye, EMT and EndMT play key roles in the pathogenesis of subretinal fibrosis, the end-stage of age-related macular degeneration (AMD) that leads to profound and permanent vision loss. Predominant in subretinal fibrotic lesions are matrix-producing mesenchymal cells believed to originate from the retinal pigment epithelium (RPE) and/or choroidal endothelial cells (CECs) through EMT and EndMT, respectively. Recent evidence suggests that EMT of RPE may also be implicated during the early stages of AMD. Transforming growth factor-beta (TGFβ) is a key cytokine orchestrating both EMT and EndMT. Investigations in the molecular mechanisms underpinning EMT and EndMT in AMD have implicated a myriad of contributing factors including signaling pathways, extracellular matrix remodelling, oxidative stress, inflammation, autophagy, metabolism and mitochondrial dysfunction. Questions arise as to differences in the mesenchymal cells derived from these two processes and their distinct mechanistic contributions to the pathogenesis of AMD. Detailed discussion on the AMD microenvironment highlights the synergistic interactions between RPE and CECs that may augment the EMT and EndMT processes in vivo. Understanding the differential regulatory networks of EMT and EndMT and their contributions to both the dry and wet forms of AMD can aid the development of therapeutic strategies targeting both RPE and CECs to potentially reverse the aberrant cellular transdifferentiation processes, regenerate the retina and thus restore vision.

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Section: Evidence and Molecular Drivers Of Emt/endmt In Amdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

Shu

Butcher

Saint‐Geniez

2020

IJMS

151

117

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“…Many of the molecular mechanisms involved in the regulation of EndMT and angiogenesis remain unknown. Nevertheless, we know that the activity of several molecules, including NRP1 (Oh et al, 2002;Matkar et al, 2016), SNAI1 (Sun et al, 2018), SNAI2 (Welch-Reardon et al, 2015),n WNT5b (Wang et al, 2017a), and WNT7a (Howe et al, 2003;Pahnke et al, 2016) induce both EC activation and EndMT. Furthermore, TWIST1 (Mammoto et al, 2018), ZEB1 (Sanchez-Tillo et al, 2010), and ZEB2 (DaSilva-Arnold et al, 2018) induce EndMT and are not known to be involved in EC activation during angiogenesis.…”

Section: The Model As Theoretical Frameworkmentioning

confidence: 99%

A Computational Model of the Endothelial to Mesenchymal Transition

2020

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Endothelial cells (ECs) form the lining of lymph and blood vessels. Changes in tissue requirements or wounds may cause ECs to behave as tip or stalk cells. Alternatively, they may differentiate into mesenchymal cells (MCs). These processes are known as EC activation and endothelial-to-mesenchymal transition (EndMT), respectively. EndMT, Tip, and Stalk EC behaviors all require SNAI1, SNAI2, and Matrix metallopeptidase (MMP) function. However, only EndMT inhibits the expression of VE-cadherin, PECAM1, and VEGFR2, and also leads to EC detachment. Physiologically, EndMT is involved in heart valve development, while a defective EndMT regulation is involved in the physiopathology of cardiovascular malformations, congenital heart disease, systemic and organ fibrosis, pulmonary arterial hypertension, and atherosclerosis. Therefore, the control of EndMT has many promising potential applications in regenerative medicine. Despite the fact that many molecular components involved in EC activation and EndMT have been characterized, the system-level molecular mechanisms involved in this process have not been elucidated. Toward this end, hereby we present Boolean network model of the molecular involved in the regulation of EC activation and EndMT. The simulated dynamic behavior of our model reaches fixed and cyclic patterns of activation that correspond to the expected EC and MC cell types and behaviors, recovering most of the specific effects of simple gain and loss-of-function mutations as well as the conditions associated with the progression of several diseases. Therefore, our model constitutes a theoretical framework that can be used to generate hypotheses and guide experimental inquiry to comprehend the regulatory mechanisms behind EndMT. Our main findings include that both the extracellular microevironment and the pattern of molecular activity within the cell regulate EndMT. EndMT requires a lack of VEGFA and sufficient oxygen in the extracellular microenvironment as well as no FLI1 and GATA2 activity within the cell. Additionally Tip cells cannot undergo EndMT directly. Furthermore, the specific conditions that are sufficient to trigger EndMT depend on the specific pattern of molecular activation within the cell.

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“…To explore the upstream regulatory mechanism underlying Bag5 downregulation in response to catecholamine treatment (Knief, Lazar-Karsten, Wellner, Hummel, & Thorns, 2019;J. X.…”

Section: Bag5 Expression Is Regulated By Mitogen-activated Protein mentioning

confidence: 99%

Bcl‐2‐associated athanogene 5 overexpression attenuates catecholamine‐induced vascular endothelial cell apoptosis

Zhu

Zhao

Chen

et al. 2020

Journal Cellular Physiology

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Bcl-2 associated athanogene 5 (Bag5) is a novel endoplasmic reticulum (ER) regulator. However, its role in catecholamine-induced endothelial cells damage has not been fully understood. In our study, catecholamine was used to mimic hypertensionrelated endothelial cell damage. Then, western blots, enzyme-linked immunosorbent assay, immunofluorescence, quantitative polymerase chain reaction and pathway analysis were conducted to analyze the role of Bag5 in endothelial cell damage in response to catecholamine. Our results indicated that the endothelial cell viability was impaired by catecholamine. Interestingly, Bag5 overexpression significantly reversed endothelial cell viability. Mechanistically, Bag5 overexpression inhibited ER stress, attenuated oxidative stress and repressed inflammation in catecholaminetreated endothelial cells. These beneficial effects finally contributed to endothelial cell survival under catecholamine treatment. Pathway analysis demonstrated that Bag5 was under the control of the mitogen-activated protein kinase (MAPK)-extracellular-signal-regulated kinase (ERK) signaling pathway. Reactivation of the MAPK-ERK pathway could upregulate Bag5 expression and thus promote endothelial cell survival through inhibiting oxidative stress, ER stress, and inflammation. Altogether, our results illustrate that Bag5 overexpression sustains endothelial cell survival in response to catecholamine treatment. This finding identifies Bag5 downregulation and the inactivated MAPK-ERK pathway as potential mechanisms underlying catecholamine-induced endothelial cell damage.

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SNAI1, an endothelial–mesenchymal transition transcription factor, promotes the early phase of ocular neovascularization

Cited by 37 publications

References 48 publications

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration

A Computational Model of the Endothelial to Mesenchymal Transition

Bcl‐2‐associated athanogene 5 overexpression attenuates catecholamine‐induced vascular endothelial cell apoptosis

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