EVL regulates VEGF receptor‐2 internalization and signaling in developmental angiogenesis

Zink, Joana; Frye, Maike; Frömel, Timo; Carlantoni, Claudia; John, David; Schreier, Danny; Weigert, Andreas; Laban, Hebatullah; Salinas, Gabriela; Stingl, Heike; Günther, Lea; Popp, Rüdiger; Hu, Jiong; Vanhollebeke, Benoît; Schmidt, Hannes; Acker‐Palmer, Amparo; Renné, Thomas; Fleming, Ingrid; Benz, P.

doi:10.15252/embr.201948961

Cited by 21 publications

(31 citation statements)

References 76 publications

(111 reference statements)

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“…Next, we sought to gain further insight into the molecular mechanisms underlying our findings. Recent studies have revealed a correlation between mitogen-activated protein kinase (MAPK) signaling pathway and EVL [ 38 , 39 ]. Based on this finding, we conducted the following sets of experiments.…”

Section: Resultsmentioning

confidence: 99%

EVL Promotes Osteo-/Odontogenic Differentiation of Dental Pulp Stem Cells via Activating JNK Signaling Pathway

Zeng

Kang

et al. 2023

Stem Cells International

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Objective. Human dental pulp stem cells (hDPSCs) were recognized as a suitable and promising source of stem cells in dental pulp regeneration. However, the mechanism by which hDPSCs differentiation into osteo-/odontogenic lineage remains unclear. Ena/VASP-like protein (EVL) has been found to be involved in diverse biological processes. In this study, we explored the role and underlying mechanism of EVL in osteo-/odontogenic differentiation of hDPSCs. Methods. Expression of EVL was detected in hDPSCs by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot (WB) analyses during osteo-/odontogenic differentiation. The function of EVL in osteo-/odontogenic differentiation and involvement of MAPK signaling pathways were evaluated by alkaline phosphatase (ALP) staining and activity, alizarin red staining (ARS), and qRT-PCR and western blot analyses. Results. The expression of EVL was upregulated during osteo-/odontogenic differentiation of hDPSCs. Overexpression of EVL significantly increased osteo-/odontogenic capacity of hDPSCs, which was reflected in increased alkaline phosphatase (ALP) staining, ALP activity, mineralized nodule formation, and the expressions of genes related to osteo-/odontogenic differentiation, while downregulation of EVL inhibited it. In addition, EVL activated the JNK pathway and phosphorylation of p38 MAPK during differentiation procedure of hDPSCs. The EVL-enhanced differentiation of DPSCs was suppressed by blocking the JNK pathway, rather than the p38 MAPK pathway. Conclusion. EVL promotes the osteo-/odontogenic differentiation of hDPSCs by activating the JNK pathway, providing a future target for osteo-/odontogenic differentiation and dental pulp regeneration.

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Section: Resultsmentioning

confidence: 99%

EVL Promotes Osteo-/Odontogenic Differentiation of Dental Pulp Stem Cells via Activating JNK Signaling Pathway

Zeng

Kang

et al. 2023

Stem Cells International

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“…Meanwhile, KEGG analysis identified axon guidance signaling as the most significantly enriched pathway between the 20 nm MPs and untreated groups. Axon guidance molecules act as key regulators of vascular guidance, 37 while their abnormal expression prevents the guided directional migration of ECs. 38…”

Section: Discussionmentioning

confidence: 99%

Multi-omics analysis reveals size-dependent toxicity and vascular endothelial cell injury induced by microplastic exposurein vivoandin vitro

Zhang

Shi

Huang

et al. 2022

Environ. Sci.: Nano

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“…Ligand-induced, clathrin-dependent VEGFR2 internalization is the initial cellular process for downstream activation of VEGFR2 signaling ( 8 – 12 ), which leads to sprouting angiogenesis, including tip EC induction ( 13 , 14 ). Our in vivo VEGFR2 internalization analysis using growing retinal vessels convincingly demonstrated that endothelial Nf2 deletion prolongs VEGF internalization into the ECs during sprouting angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…High Notch signaling activity inhibits tip EC behaviors while promoting the stalk cell phenotype (6,7). Molecularly, ligand-induced, clathrin-dependent VEGF receptor 2 (VEGFR2) internalization is the initial process for intracellular activation of VEGFR2 signaling (8)(9)(10)(11)(12), while, morphologically, tip EC induction is a foremost step for sprouting angiogenesis (13,14). However, a persistent puzzle is how one particular EC has higher VEGFR2 signaling activity than its neighbors and is thus fated to become a tip EC during sprouting angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Gatekeeping role of Nf2 /Merlin in vascular tip EC induction through suppression of VEGFR2 internalization

et al. 2022

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In sprouting angiogenesis, the precise mechanisms underlying how intracellular vascular endothelial growth factor receptor 2 (VEGFR2) signaling is higher in one endothelial cell (EC) compared with its neighbor and acquires the tip EC phenotype under a similar external cue are elusive. Here, we show that Merlin, encoded by the neurofibromatosis type 2 ( NF2 ) gene, suppresses VEGFR2 internalization depending on VE-cadherin density and inhibits tip EC induction. Accordingly, endothelial Nf2 depletion promotes tip EC induction with excessive filopodia by enhancing VEGFR2 internalization in both the growing and matured vessels. Mechanistically, Merlin binds to the VEGFR2–VE-cadherin complex at cell-cell junctions and reduces VEGFR2 internalization–induced downstream signaling during tip EC induction. As a consequence, nonfunctional excessive sprouting occurs during tumor angiogenesis in EC-specific Nf2 -deleted mice, leading to delayed tumor growth. Together, Nf2 /Merlin is a crucial molecular gatekeeper for tip EC induction, capillary integrity, and proper tumor angiogenesis by suppressing VEGFR2 internalization.

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EVL regulates VEGF receptor‐2 internalization and signaling in developmental angiogenesis

Cited by 21 publications

References 76 publications

EVL Promotes Osteo-/Odontogenic Differentiation of Dental Pulp Stem Cells via Activating JNK Signaling Pathway

EVL Promotes Osteo-/Odontogenic Differentiation of Dental Pulp Stem Cells via Activating JNK Signaling Pathway

Multi-omics analysis reveals size-dependent toxicity and vascular endothelial cell injury induced by microplastic exposurein vivoandin vitro

Gatekeeping role of Nf2 /Merlin in vascular tip EC induction through suppression of VEGFR2 internalization

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