Connexin37 reduces smooth muscle cell proliferation and intimal hyperplasia in a mouse model of carotid artery ligation

Allagnat, Florent; Dubuis, Céline; Lambelet, Martine; Gal, Loïc Le; Alonso, Florian; Corpataux, Jean-Marc; Déglise, Sebastien; Haefliger, Jacques-Antoine

doi:10.1093/cvr/cvx079

Cited by 37 publications

(51 citation statements)

References 50 publications

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“…Cx37 exerts a growth suppressive effect in vivo and in vitro; it suppresses vasculogenesis and angiogenesis (Allagnat et al, 2017;Fang et al, 2011) and is a potent suppressor of cancer cell proliferation (Burt et al, 2008;Morel et al, 2010). Available data (Good et al, 2012(Good et al, , 2014(Good et al, , 2011Nelson et al, 2013) suggest:…”

Section: Discussionmentioning

confidence: 99%

Regulation of Cx37 channel and growth-suppressive properties by phosphorylation

Jacobsen

Pontifex

et al. 2017

Journal of Cell Science

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Growth suppression mediated by connexin 37 (Cx37; also known as GJA4) requires interaction between its C-terminus and functional pore-forming domain. Using rat insulinoma cells, we show that Cx37 induces cell death and cell cycle arrest, and slowed cell cycling. Whether differential phosphorylation might regulate intramolecular interactions, and consequently the growth-suppressive phenotype, is unknown. Protein kinase C inhibition increased the open state probability of low-conductance gap junction channels (GJChs) and reduced GJCh closed state probability. Substituting alanine at serine residues 275, 302 and 328 eliminated Cx37-induced cell death, supported proliferation and reduced the GJCh closed state probability. With additional alanine for serine substitutions at residues 285, 319, 321 and 325, Cx37-induced cell death was eliminated and the growth arrest period prolonged, and GJCh closed state probability was restored. With aspartate substitution at these seven sites, apoptosis was induced and the open state probability of large conductance GJChs (and hemichannels) was increased. These data suggest that differential phosphorylation of the C-terminus regulates channel conformation and, thereby, cell cycle progression and cell survival.

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Section: Discussionmentioning

confidence: 99%

Regulation of Cx37 channel and growth-suppressive properties by phosphorylation

Jacobsen

Pontifex

et al. 2017

Journal of Cell Science

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“…However, studies have suggested that DESs delay re-endothelialization, which is important for the prevention of restenosis and stent thrombosis. Intimal hyperplasia develops as a result of SMC migration and proliferation, and the accumulation of the extracellular matrix, which is a normal adaptive response in arteries against hemodynamic stress and is a characteristic feature of arterial injury healing ( 15 , 16 ).…”

Section: Discussionmentioning

confidence: 99%

The effect of anagliptin on intimal hyperplasia of rat carotid artery after balloon injury

et al. 2017

Molecular Medicine Reports

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The present study evaluated the effect of anagliptin on intimal hyperplasia following carotid artery injury in Sprague-Dawley rats. Sprague-Dawley rats weighing 280–300 g were injured using a 2F Fogarty balloon embolectomy catheter. The rats were divided into injury-(saline) and anagliptin-(10 mg/kg/day) treated groups. vascular injuries were induced in the left carotid artery, followed by evaluation of neointima formation at 28 days. The right and left carotid arteries were harvested and evaluated with histological evaluation, and the plasma activity of glucagon-like peptide 1 receptor (GLP-1), stromal cell-derived factor (SDF)-1α, interleukin (IL)-6, IL-1β and tumor necrosis factor (TNF)-α were detected by ELISA analysis. Treatment with anagliptin decreased balloon injury-induced neointima formation, compared with the injury group (P<0.01). Body weight and food consumption did not alter following treatment with anagliptin. Anagliptin caused an increase in the serum active GLP-1 concentration, compared with the injury group. In addition, serum SDF-1α was significantly decreased by treatment with anagliptin (P<0.001). Anagliptin altered the serum activity of IL-6, IL-1β and TNF-α (P<0.01). The results of the present study demonstrated that anagliptin appeared to attenuate neointimal formation by inhibiting inflammatory cytokines and chemokines following balloon injury, and that treatment with a dipeptidyl peptidase 4 inhibitor may be useful for future preclinical studies and potentially for the inhibition of thrombosis formation following percutaneous coronary intervention.

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“…Nitric oxide (NO) has anti-inflammatory effects and protects against neointimal hyperplasia [22]. Therefore, we assessed the expression of NO synthase mRNA by RT-PCR.…”

Section: Hucmsc-exosomes Significantly Accelerated Reendothelializatimentioning

confidence: 99%

Exosomes derived from human umbilical cord mesenchymal stem cells inhibit vein graft intimal hyperplasia and accelerate reendothelialization by enhancing endothelial function

Pang

Zhang

et al. 2020

Stem Cell Res Ther

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Background: In our previous research, we found that mesenchymal stem cell (MSC) transplantation therapy can inhibit intimal hyperplasia and enhance endothelial function in arterialized vein grafts in rats. However, whether MSC-derived exosomes (MSC-exosomes) can reduce neointimal formation and its possible mechanism is still unclear.Methods: The primary human umbilical cord MSCs (hucMSCs) and human umbilical vein endothelial cells (HUVECs) were isolated and characterized by flow cytometry and immunofluorescence. The exosomes derived from hucMSCs (hucMSC-exosomes) were identified by transmission electron microscopy and western blots. hucMSC-exosomes were intravenously injected into a rat model of vein grafting, and its effect on vein grafts reendothelialization and intimal hyperplasia was assessed by physical, histological, immunohistochemistry, and immunofluorescence examinations. The effects of hucMSC-exosomes on endothelial cells were evaluated by integrated experiment, EdU staining, scratch assay, and Transwell assay. The expression levels of key gene and pathways associated with the biological activity of vascular endothelial cells were evaluated following the stimulation of hucMSC-exosomes. Results: We successfully isolated and characterized primary hucMSCs and hucMSC-exosomes and primary HUVECs. We verified that the systemic administration of hucMSC-exosomes accelerates reendothelialization and decreases intimal hyperplasia of autologous vein graft in a rat model. We also identified that hucMSC-exosomes can be uptaken by endothelial cells to stimulate cell proliferative and migratory activity in vitro. Furthermore, we detected that vascular endothelial growth factor (VEGF) plays an important part in hucMSC-exosome-mediated proliferation and migration in HUVECs. In addition, we also provided evidence that the signalling pathways of PI3K/AKT and MAPK/ERK1/2 take part in hucMSC-exosome-induced VEGF regulation.(Continued on next page) Conclusion: Our data suggest that hucMSC-exosomes exert a vasculoprotective role in the setting of vein graft disease, which may provide a new clue to protect against vein graft failure in the future.

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Connexin37 reduces smooth muscle cell proliferation and intimal hyperplasia in a mouse model of carotid artery ligation

Abstract: The presence of Cx37 in the media layer of injured arteries restrains VSMC proliferation and limits the development of IH, presumably by interfering with the pro-proliferative effect of Cx43 and the Akt pathway.

Cited by 37 publications

References 50 publications

Regulation of Cx37 channel and growth-suppressive properties by phosphorylation

Regulation of Cx37 channel and growth-suppressive properties by phosphorylation

The effect of anagliptin on intimal hyperplasia of rat carotid artery after balloon injury

Exosomes derived from human umbilical cord mesenchymal stem cells inhibit vein graft intimal hyperplasia and accelerate reendothelialization by enhancing endothelial function

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