Isoform-Specific Roles of ERK1 and ERK2 in Arteriogenesis

Ricard, Nicolas; Zhang, Jiasheng; Zhuang, Zhen W.; Simons, Michael

doi:10.3390/cells9010038

Cited by 20 publications

(17 citation statements)

References 49 publications

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“…Global ERK1 knockout mice are viable [48], whereas global ERK2 knockout in mice results in embryonic lethality [49], suggesting that ERK1 and ERK2 perform distinct roles in several tissues, including the vasculature. Recently, Ricard and colleagues demonstrated that loss of ERK2 in murine endothelial cells decreased arteriogenesis, whereas loss of endothelial ERK1 resulted in increased but poorly functional arteriogenesis [50]. Our findings reiterate this vasculoprotective role of ERK2.…”

Section: Discussionsupporting

confidence: 84%

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice

Menon

Shrestha

Barrios

et al. 2020

IJMS

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Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a significant lung morbidity of infants, and disrupted lung angiogenesis is a hallmark of this disease. We observed that extracellular signal-regulated kinases (ERK) 1/2 support angiogenesis in vitro, and hyperoxia activates ERK1/2 in fetal human pulmonary microvascular endothelial cells (HPMECs) and in neonatal murine lungs; however, their role in experimental BPD and PH is unknown. Therefore, we hypothesized that Tie2 Cre-mediated deficiency of ERK2 in the endothelial cells of neonatal murine lungs would potentiate hyperoxia-induced BPD and PH. We initially determined the role of ERK2 in in vitro angiogenesis using fetal HPMECs. To disrupt endothelial ERK2 signaling in the lungs, we decreased ERK2 expression by breeding ERK2flox/flox mice with Tie-Cre mice. One-day-old endothelial ERK2-sufficient (eERK2+/+) or –deficient (eERK2+/−) mice were exposed to normoxia or hyperoxia (FiO2 70%) for 14 d. We then performed lung morphometry, gene and protein expression studies, and echocardiography to determine the extent of inflammation, oxidative stress, and development of lungs and PH. The knockdown of ERK2 in HPMECs decreased in vitro angiogenesis. Hyperoxia increased lung inflammation and oxidative stress, decreased lung angiogenesis and alveolarization, and induced PH in neonatal mice; however, these effects were augmented in the presence of Tie2-Cre mediated endothelial ERK2 deficiency. Therefore, we conclude that endothelial ERK2 signaling is necessary to mitigate hyperoxia-induced experimental BPD and PH in neonatal mice. Our results indicate that endothelial ERK2 is a potential therapeutic target for the management of BPD and PH in infants.

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Section: Discussionsupporting

confidence: 84%

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice

Menon

Shrestha

Barrios

et al. 2020

IJMS

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“…80 ), DLL-4 (refs. 81,82 ), and ERK [83][84][85] signaling are all involved in arteriogenesis and we indeed observed a defect in the patterning of veins and arteries. A final aspect is a potential role of PRL-2 in vascular stability and pruning since empty basement membranes were increased in Ptp4a2 fl/fl iEKO.…”

Section: Discussionsupporting

confidence: 58%

PRL-2 phosphatase is required for vascular morphogenesis and angiogenic signaling

Poulet¹,

Sirois²,

Boyé³

et al. 2020

Commun Biol

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Protein tyrosine phosphatases are essential modulators of angiogenesis and have been identified as novel therapeutic targets in cancer and anti-angiogenesis. The roles of atypical Phosphatase of Regenerative Liver (PRL) phosphatases in this context remain poorly understood. Here, we investigate the biological function of PRL phosphatases in developmental angiogenesis in the postnatal mouse retina and in cell culture. We show that endothelial cells in the retina express PRL-2 encoded by the Ptp4a2 gene, and that inducible endothelial and global Ptp4a2 mutant mice exhibit defective retinal vascular outgrowth, arteriovenous differentiation, and sprouting angiogenesis. Mechanistically, PTP4A2 deletion limits angiogenesis by inhibiting endothelial cell migration and the VEGF-A, DLL-4/NOTCH-1 signaling pathway. This study reveals the importance of PRL-2 as a modulator of vascular development.

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“…Furthermore, the Erk signalling pathway is a prototypic mitogenactivated protein kinase (MAPK) signalling cascade that is involved in cell survival, proliferation, migration and differentiation [45,46]. Several studies also showed that the Erk signalling pathway was closely associated with the growth, survival and migration of cells, whereas these effects were reversed when the signalling pathway was blocked using corresponding inhibitors [47,48]. Thus, we hypothesized that MSC-Exo could activate/inactivate the Erk signalling pathway during the proliferation and migration of EC.…”

Section: Discussionmentioning

confidence: 99%

Exosomes derived from mesenchymal stem cells inhibit neointimal hyperplasia by activating the Erk1/2 signalling pathway in rats

Liu

Zou

et al. 2020

Stem Cell Res Ther

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Background: Restenosis is a serious problem in patients who have undergone percutaneous transluminal angioplasty. Endothelial injury resulting from surgery can lead to endothelial dysfunction and neointimal formation by inducing aberrant proliferation and migration of vascular smooth muscle cells. Exosomes secreted by mesenchymal stem cells have been a hot topic in cardioprotective research. However, to date, exosomes derived from mesenchymal stem cells (MSC-Exo) have rarely been reported in association with restenosis after artery injury. The aim of this study was to investigate whether MSC-Exo inhibit neointimal hyperplasia in a rat model of carotid artery balloon-induced injury and, if so, to explore the underlying mechanisms. Methods: Characterization of MSC-Exo immunophenotypes was performed by electron microscopy, nanoparticle tracking analysis and western blot assays. To investigate whether MSC-Exo inhibited neointimal hyperplasia, rats were intravenously injected with normal saline or MSC-Exo after carotid artery balloon-induced injury. Haematoxylin-eosin staining was performed to examine the intimal and media areas. Evans blue dye staining was performed to examine re-endothelialization. Moreover, immunohistochemistry and immunofluorescence were performed to examine the expression of CD31, vWF and α-SMA. To further investigate the involvement of MSC-Exoinduced re-endothelialization, the underlying mechanisms were studied by cell counting kit-8, cell scratch, immunofluorescence and western blot assays. Results: Our data showed that MSC-Exo were ingested by endothelial cells and that systemic injection of MSC-Exo suppressed neointimal hyperplasia after artery injury. The Evans blue staining results showed that MSC-Exo could accelerate re-endothelialization compared to the saline group. The immunofluorescence and immunohistochemistry results showed that MSC-Exo upregulated the expression of CD31 and vWF but downregulated the expression of α-SMA. Furthermore, MSC-Exo mechanistically facilitated proliferation and migration by activating the Erk1/2 signalling pathway. The western blot results showed that MSC-Exo upregulated the expression of PCNA, Cyclin D1, Vimentin, MMP2 and MMP9 compared to that in the control group.

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Isoform-Specific Roles of ERK1 and ERK2 in Arteriogenesis

Cited by 20 publications

References 49 publications

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice

Tie-2 Cre-Mediated Deficiency of Extracellular Signal-Regulated Kinase 2 Potentiates Experimental Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension in Neonatal Mice

PRL-2 phosphatase is required for vascular morphogenesis and angiogenic signaling

Exosomes derived from mesenchymal stem cells inhibit neointimal hyperplasia by activating the Erk1/2 signalling pathway in rats

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