Neuregulin-1 Signaling in Brain Endothelial Cells

Lok, Josephine; Sardi, S. Pablo; Guo, Shuzhen; Besancon, Elaine; Ha, Duy M.; Rosell, Anna; Kim, Woo Jean; Corfas, Gabriel; Lo, Eng H.

doi:10.1038/jcbfm.2008.94

Cited by 44 publications

(37 citation statements)

References 15 publications

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“…S1). The erbB receptor complement of EPCs (erbB2ϩ/ erbB3ϩ/erbB4Ϫ) is consistent with that of mature ECs (8,27). Another interesting similarity is that eEPCs, like mature ECs, express NRG-1 ligand.…”

Section: Discussionsupporting

confidence: 62%

“…Although upregulation of VEGF expression may, in part, explain the NRG-dependent angiogenic effect, there is evidence for a VEGF-independent effect of NRG on angiogenesis (35). In human brain microvascular ECs NRG treatment protects against oxidant injury, indicating that NRG regulates endothelial homeostasis in "normal" (e.g., noncancerous) tissues as well (27). These data indicate a potential role for NRG/erbB signaling in regulation of vascular homeostasis.…”

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confidence: 95%

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Neuregulin-1β regulation of embryonic endothelial progenitor cell survival

Safa

Peng

Pentassuglia

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Endothelial progenitor cells (EPCs) are mobilized into the vascular space and home to damaged tissues, where they promote repair in part through a process of angiogenesis. Neuregulins (NRGs) are ligands in the epidermal growth factor family that signal through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3, and erbB4) and regulate endothelial cell biology, promoting angiogenesis. Stimuli such as ischemia and exercise that promote EPC mobilization also induce cleavage and release of transmembrane NRG from cardiac microvascular endothelial cells (CMECs). We hypothesized that NRG/erbB signaling may regulate EPC biology. Using an embryonic (e)EPC cell line that homes to and repairs injured myocardium, we were able to detect erbB2 and erbB3 transcripts. Identical receptor expression was found in EPCs isolated from rat bone marrow and human whole blood. NRG treatment of eEPCs induces phosphorylation of kinases including Akt, GSK-3β, and Erk1/2 and the nuclear accumulation and transcriptional activation of β-catenin. NRG does not induce eEPC proliferation or migration but does protect eEPCs against serum deprivation-induced apoptosis. These results suggest a role for tissue-derived NRG in the regulation of EPC survival.

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Section: Discussionsupporting

confidence: 62%

mentioning

confidence: 95%

Neuregulin-1β regulation of embryonic endothelial progenitor cell survival

Safa

Peng

Pentassuglia

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…ErbB receptors are expressed in EPCs, and NRG-1 stimulation can enhance EPCs survival and their participation in angiogenic responses [28]. Lok et al reported that NRG-1 can decrease human brain endothelial cells death after oxidative injury with H 2 O 2 [29]. Oxidative stress caused by mitochondrial superoxide overproduction in endothelial cells is the major mechanism in the development of vascular complications in diabetes [30, 31].…”

Section: Discussionmentioning

confidence: 99%

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

Gui

Zeng

Chen³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Microvascular insufficiency takes a critical role in the development of diabetic cardiomyopathy (DCM). So this study was designed to investigate the effects of Neuregulin-1 (NRG-1) treatment on myocardial angiogenesis and the changes of VEGF/Flk1 and Ang-1/Tie-2 signaling in the rat model of DCM. Methods: Diabetic rats were induced by a single intraperitoneal injection of Streptozotocin. 12 weeks after the diabetes induction, the rats with NRG-1 treatment were treated with tail vein injection of NRG-1 at the dose of 10µg/kg/d for consecutive 10 days. Cardiac function was assessed using catheter MPA cardiac function analysis system. Myocardial blood flow (MBF) was assessed with stable-isotope labeled microspheres. Capillary density was measured by CD31 immunohistochemistry. The protein expression and receptors phosphorylation were assessed using western blot. Results: Left ventricular function, capillary density and MBF were significantly reduced in DCM group when compared with those in the control group (P< 0.01, P< 0.01 and P< 0.05 respectively). Left ventricular function and capillary density were significantly increased in NRG-1 treatment group when compared with those in the DCM group (P< 0.05 and P< 0.05 respectively). The expression of VEGF and Ang-1 and the phosphorylation of Flk1 and Tie-1 were significantly decreased in DCM group as compared with those in the control group. However, those in the NRG-1 treatment group were significantly increased as compared with those in the DCM group. In vitro, NRG-1 treatment increased significantly the expression of VEGF and Ang-1 in human coronary artery smooth muscle cells. Conclusions: NRG-1 can increase the myocardial angiogenesis of DCM, probably via the direct effects of NRG-1 and via the increasing expression of VEGF and Ang-1. These findings may contribute to developing a novel approach to reverse the impaired angiogenic responses in diabetes or coronary artery disease.

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“…58,59 NRG-1β exerts a cytoprotective effect against oxidant injury in multiple cell types in the brain, including the microvascular endothelial cell. 60 …”

Section: Nrg In the Central And Peripheral Nervous System: Implicatiomentioning

confidence: 99%

Neuregulin in Cardiovascular Development and Disease

Odiete

Hill

Sawyer

2012

Circulation Research

240

203

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Studies in genetically modified mice have demonstrated that neuregulin-1 (NRG-1), along with the erythroblastic leukemia viral oncogene homolog (ErbB) 2, 3, and 4 receptor tyrosine kinases, is necessary for multiple aspects of cardiovascular development. These observations stimulated in vitro and in vivo animal studies, implicating NRG-1/ErbB signaling in the regulation of cardiac cell biology throughout life. Cardiovascular effects of ErbB2-targeted cancer therapies provide evidence in humans that ErbB signaling plays a role in the maintenance of cardiac function. These and other studies suggest a conceptual model in which a key function of NRG-1/ErbB signaling is to mediate adaptations of the heart to physiological and pathological stimuli through activation of intracellular kinase cascades that regulate tissue plasticity. Recent work implicates NRG-1/ErbB signaling in the regulation of multiple aspects of cardiovascular biology, including angiogenesis, blood pressure, and skeletal muscle responses to exercise. The therapeutic potential of recombinant NRG-1 as a potential treatment for heart failure has been demonstrated in animal models and is now being explored in clinical studies. NRG-1 is found in human serum and plasma, and it correlates with some clinical parameters, suggesting that it may have value as an indicator of prognosis. In this review, we bring together this growing literature on NRG-1 and its significance in cardiovascular development and disease.

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Neuregulin-1 Signaling in Brain Endothelial Cells

Cited by 44 publications

References 15 publications

Neuregulin-1β regulation of embryonic endothelial progenitor cell survival

Neuregulin-1β regulation of embryonic endothelial progenitor cell survival

Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy

Neuregulin in Cardiovascular Development and Disease

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