Calcitonin gene-related peptide promotes angiogenesis via AMP-activated protein kinase

Zheng, Shuai; Li, Wenjing; Xu, Mingjiang; Bai, Xue; Zhou, Zhou; Han, Jing‐Yan; Shyy, John Y.‐J.; Wang, Xian

doi:10.1152/ajpcell.00173.2010

Cited by 68 publications

(72 citation statements)

References 40 publications

(39 reference statements)

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“…It was revealed that apelin is expressed in vascular endothelial cells and participates in regulating their proliferation and regenerative angiogenesis (22,23,24). Calcitonin gene-related peptide and vascular endothelial growth factor were reported to promote angiogenesis by promoting AMPK and Akt signaling activation, respectively (25,26). AMPK and Akt directly phosphorylate eNOS (17,27), which is important in angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Apelin-13 stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in myocardial microvascular endothelial cells

Yang

Zhu

Zhang

et al. 2014

Molecular Medicine Reports

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Abstract. Currently, there is major interest in the functions of apelin-13, an endogenous ligand for the orphan G-protein coupled receptor APJ, a receptor that closely resembles the angiotensin receptor AT1. In the present study, the role of apelin-13 in angiogenesis and its mechanism as a novel angiogenic factor in myocardial microvascular endothelial cells (MMVECs) was investigated. It was revealed that apelin-13 can promote proliferation, migration and tube formation in MMVECs. In addition, apelin-13 dose dependently stimulated the phosphorylation of AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) at Thr-172 and Ser-1179, respectively. The treatment with the AMPK (compound C) and protein kinase Akt/protein kinase B (Akt; LY294002) inhibitor significantly suppressed the apelin-13-induced AMPK, Akt and eNOS phosphorylation. They also inhibited the apelin13-stimulated endothelial cell migration and tube formation. Therefore, we hypothesize that apelin-13 promotes angiogenesis through the modulation of AMPK and Akt signaling in MMVECs.

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Section: Discussionmentioning

confidence: 99%

Apelin-13 stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in myocardial microvascular endothelial cells

Yang

Zhu

Zhang

et al. 2014

Molecular Medicine Reports

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“…Increasing intracellular cAMP and calcium leads to changes in cell morphology and function [42,43] , but the effect of cAMP signaling on CGRP-dependent BMP-2 expression remains unclear. To examine these events, we examined the synthesis of BMP-2 mRNA and protein after pretreatment with the cAMP pathway inhibitor H-89.…”

Section: Discussionmentioning

confidence: 99%

Calcitonin gene-related peptide stimulates BMP-2 expression and the differentiation of human osteoblast-like cells in vitro

2013

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Aim: To investigate whether bone morphogenic protein-2 (BMP-2) expression was involved in calcitonin gene-related peptide (CGRP)-induced osteogenesis in human osteoblast-like cells in vitro. Methods: MG-63 osteogenic human osteosarcoma cells were treated with CGRP (10 -8 mol/L) for 48 h. Cell cycle phases were determined using flow cytometry assay. The protein levels of BMP-2, ALP, Osteocalcin, ColIa1, CREB, and pCREB were measured with Western blotting, while the mRNA level of BMP-2 was measured with qR-T PCR. The expression of ALP in MG-63 cells was also studied using immunofluorescence staining. The level of cAMP was measured with ELISA assay. Results: CGRP treatment significantly stimulated proliferation of MG-63 cells, and increased the expression of BMP-2 and the osteogenic proteins ALP, Osteocalcin and ColIa1. Pretreatment with the BMP signaling inhibitor Noggin (100 ng/mL) did not affect CGRPstimulated proliferation and BMP-2 expression, but abolished the CGRP-induced increases of the osteogenic proteins ALP, Osteocalcin and ColIa1. Furthermore, CGRP treatment markedly increased cAMP level in MG-63 cells, whereas pretreatment with the cAMP pathway inhibitor H89 (5 μmol/L) abolished the CGRP-induced increases of cAMP level and BMP-2 expression. Conclusion: In MG-63 cells, the BMP pathway is involved in CGRP-induced osteogenic differentiation but not in proliferation, whereas the cAMP/pCREB pathway is involved in the expression of BMP-2.Keywords: c calcitonin gene-related peptide; Noggin; H89; MG-63 human osteosarcoma cell; osteogenesis; bone morphogenic protein; cAMP/pCREB pathway Acta Pharmacologica Sinica (2013Sinica ( ) 34: 1467Sinica ( -1474 doi: 10.1038/aps.2013 published online 27 May 2013 Original Article IntroductionSensory nerve activation has a centrally mediated but poorly understood action on bone. The relative importance and interactions between autonomic, sensory, and peripheral nervous system actions on bone mass are not clear in healthy individuals and even less so in pathologic states. Understanding how the central nervous system integrates homeostatic signals with the regulation of bone homeostasis is an exciting research area.Experimental evidence suggests that the nervous system is involved in bone remodeling. In response to fracture or other trauma, peripheral peptidergic neurons can influence osteoclast formation through the production of several neuropeptides. Calcitonin gene-related peptide (CGRP), a 37-residue peptide generated in specific neurons by alternative splicing of the calcitonin gene, is an important neuropeptide expressed * To whom correspondence should be addressed.E-mail tanyhoms@yahoo.cn Received 2012-10-30 Accepted 2013-03-25 in nerve fibers during bone development and repair [1,2] .Numerous in vivo studies have suggested that CGRP is associated with bone development, metabolism and repair. In vitro studies have demonstrated that CGRP stimulates osteoblast proliferation, differentiation and maturation in both osteoblast cell lines and bone marrow mesenchyme strom...

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“…Major sources of ROS are thought to be eNOS-uncoupling and NADPH oxidase [41] CGRP has been shown to activate eNOS via the cAMP-PKA [42] and AMPK [43] pathways.…”

Section: Discussionmentioning

confidence: 99%

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

Yang

Sakurai

Kamiyoshi

et al. 2013

Journal of Molecular and Cellular Cardiology

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Neointimal hyperplasia is the primary lesion underlying atherosclerosis and restenosis after percutaneous coronary intervention. Calcitonin gene-related peptide (CGRP) is produced by alternative splicing of the primary transcript of the calcitonin/CGRP gene.Originally identified as a strongly vasodilatory neuropeptide, CGRP is now known to be a pleiotropic peptide widely distributed in various organs and tissues. Our aim was to investigate the possibility that CGRP acts as an endogenous vasoprotective molecule.We compared the effect of CGRP deficiency on neointima formation after wire-induced vascular injury in wild-type and CGRP knockout (CGRP-/-) mice. We found that neointima formation after vascular injury was markedly enhanced in CGRP-/-mice, which also showed a higher degree of oxidative stress, as indicated by reduced expression of nitric oxide synthase, increased expression of p47phox, and elevated levels of 4HNE, as well as greater infiltration of macrophages. In addition, CGRP-deficiency led to increased vascular smooth muscle cell (VSMC) proliferation within the neointima. By contrast, bone marrow-derived cells had little or no effect on neointima formation in CGRP-/-mice. In vitro analysis showed CGRP-treatment suppressed VSMC proliferation, migration, and ERK1/2 activity. These results clearly demonstrate that endogenous CGRP suppresses the oxidative stress and VSMC proliferation induced by vascular injury. As a vasoprotective molecule, CGRP could be an important therapeutic target in cardiovascular disease.

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Calcitonin gene-related peptide promotes angiogenesis via AMP-activated protein kinase

Cited by 68 publications

References 40 publications

Apelin-13 stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in myocardial microvascular endothelial cells

Apelin-13 stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in myocardial microvascular endothelial cells

Calcitonin gene-related peptide stimulates BMP-2 expression and the differentiation of human osteoblast-like cells in vitro

Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury

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