Time-Variant SRC Kinase Activation Determines Endothelial Permeability Response

Klomp, Jennifer E.; Shaaya, Mark; Matsche, Jacob; Rebiai, Rima; Aaron, Jesse; Collins, Kerrie B.; Huyot, Vincent; Gonzalez, Annette M.; Müller, William A.; Chew, Teng Leong; Malik, Asrar B.; Karginov, Andrei V.

doi:10.1016/j.chembiol.2019.04.007

Cited by 26 publications

(22 citation statements)

References 68 publications

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“…Although it has other functions, the main function of VE-cadherin is to promote adhesion between endothelial cells and to increase cell permeability when junctions are disrupted 27 . The tyrosine kinase Src activates phosphorylation of VE–cadherin at the Y658 and Y731 residues 30 . VE-cadherin interacts with p120 and β-catenin through its cytoplasmic tail to promote cell adhesion 31 .…”

Section: Resultsmentioning

confidence: 99%

Anionic nanoplastic exposure induces endothelial leakiness

Wei

Lee

et al. 2022

Nat Commun

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The global-scale production of plastics has been instrumental in advancing modern society, while the rising accumulation of plastics in landfills, oceans, and anything in between has become a major stressor on environmental sustainability, climate, and, potentially, human health. While mechanical and chemical forces of man and nature can eventually break down or recycle plastics, our understanding of the biological fingerprints of plastics, especially of nanoplastics, remains poor. Here we report on a phenomenon associated with the nanoplastic forms of anionic polystyrene and poly(methyl methacrylate), where their introduction disrupted the vascular endothelial cadherin junctions in a dose-dependent manner, as revealed by confocal fluorescence microscopy, signaling pathways, molecular dynamics simulations, as well as ex vivo and in vivo assays with animal model systems. Collectively, our results implicated nanoplastics-induced vasculature permeability as primarily biophysical-biochemical in nature, uncorrelated with cytotoxic events such as reactive oxygen species production, autophagy, and apoptosis. This uncovered route of paracellular transport has opened up vast avenues for investigating the behaviour and biological effects of nanoplastics, which may offer crucial insights for guiding innovations towards a sustainable plastics industry and environmental remediation.

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Section: Resultsmentioning

confidence: 99%

Anionic nanoplastic exposure induces endothelial leakiness

Wei

Lee

et al. 2022

Nat Commun

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“…The role of SRC activity in the regulation of endothelial permeability was reported previously. Transient activation of SRC reduced the endothelial permeability due to VE-cadherin phosphorylation on Y731 [ 27 ]. Therefore, the role of Src/VE-cadherin signaling pathways in vascular permeability has received much attention.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Qingre Huayu Recipe on Wound Healing after Anal Fistulotomy in Sprague-Dawley Rats

Jiazhi

Wang

Chen

et al. 2022

Computational and Mathematical Methods in Medicine

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Anal fistula is a common anorectal disease. At present, most scholars believe that its pathogenesis is related to anal gland infection. Anal fistula cannot heal on its own after the onset and must be treated surgically. The wound of anal fistula surgery is open and polluted, and it belongs to three types of three-stage healing; it is the most difficult to heal among all surgical incisions, with a long course of disease, a lot of exudation, and pain for the patient; traditional Chinese medicine has rich experience in the treatment of postoperative wound healing of anal fistula. The study aimed to evaluate the mechanism of Qingre Huayu (QRHY) Recipe on wound healing after fistulotomy on SD rats. SD rats ( n = 72 ) were randomized into three groups post-anorectal surgery. The rats in the positive control group were given potassium permanganate (PP), treatment group were given QRHY, and trauma model group were given 0.9% normal salinity. The changes in wound secretion, granulated tissue, and epithelium tissue were observed, and wound healing rates were evaluated by the discrepancies in wound area. HE and Masson’s staining as well as transmission electron microscopy were also performed. The localization as well as the measurement of Ang1, Src, and VE cadherin expression in each group adopted real-time PCR, western blot, and immunohistochemistry (IHC) assays. Statistically higher wound healing rates were observed in QRHY group on days 3, 7, and 14 compared with other groups. Histological analyses showed highly significant increase in collagen and fibroblasts, less inflammatory cells, and vascular endothelial permeability in QRHY rats. The transmission electron microscopy revealed that the intact structure of tight junctions in endothelial cells and well-organized collagen and VE-cadherin, Ang1, and Tie-2 were upregulated by QRHY, while Src was inhibited. This study showed that QRHY can promote wound healing after anal fistulas.

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“…VE‐cadherin is a direct substrate of Src kinase which is phosphorylated by Src at residue Y 685 , 40 although it is believed that Src‐mediated phosphorylation leads only to short‐term permeability 41 …”

Section: Discussionmentioning

confidence: 99%

Downregulation of miR‐1270 mediates endothelial progenitor cell function in preeclampsia: Role for ATM in the Src/VE‐cadherin axis

et al. 2022

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Preeclampsia, a pregnancy‐related hypertensive disorder, is associated with endothelial dysfunction and increased cardiovascular risk of the offspring in adulthood. In preeclampsia, endothelial colony‐forming cells (ECFC) are reduced in number and function. Recently, we have shown that miR‐1270, which is involved in cancer in vitro proliferation, migration, and tumor progression, is downregulated in fetal ECFC from preeclamptic pregnancies. We now hypothesize that miR‐1270 dysregulation contributes to vascular endothelial dysfunction occurring after preeclampsia via ATM (ataxia telangiectasia mutated) overexpression, the key kinase of DNA damage repair. Here, we show that miR‐1270 silencing in normal ECFC and downregulation in preeclamptic ECFC are accompanied by an increase in the expression levels of ATM. Furthermore, ATM activation correlates with upregulated tyrosine kinase Src leading to phosphorylation and internalization of VE‐cadherin (vascular endothelial‐cadherin) which subsequently compromises endothelial barrier permeability and morphodynamic cell parameters. Treatment with specific ATM inhibitors reveals a novel role of ATM upstream of tyrosine kinase Src activation. Subsequently, Src phosphorylation and internalization of VE‐cadherin compromise endothelial barrier permeability. Our findings suggest that downregulation of miR‐1270 contributes to impaired ECFC function via the associated ATM overexpression, which further identifies ATM as a novel and critical factor for ECFC defects in preeclampsia. Our study provides new insights into the understanding of ECFC impairment associated with cardiovascular risk in preeclamptic offspring and identifies potential novel therapeutic targets.

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Time-Variant SRC Kinase Activation Determines Endothelial Permeability Response

Cited by 26 publications

References 68 publications

Anionic nanoplastic exposure induces endothelial leakiness

Anionic nanoplastic exposure induces endothelial leakiness

The Effect of Qingre Huayu Recipe on Wound Healing after Anal Fistulotomy in Sprague-Dawley Rats

Downregulation of miR‐1270 mediates endothelial progenitor cell function in preeclampsia: Role for ATM in the Src/VE‐cadherin axis

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