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

Yang, Xiaoman; Zhu, Wei; Zhang, Pu; Chen, Kankai; Zhao, Lijie; Li, Jingbo; Wang, Meng; Liu, Mingya

doi:10.3892/mmr.2014.1984

Cited by 33 publications

(25 citation statements)

References 32 publications

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“…In agreement, chronic administration of the native apelin peptide reduced RVSP in mouse and rat models of PAH (Alastalo et al, 2011;Falcão-Pires et al, 2009). AMPK mediated the pro-angiogenic effects of apelin and activation of AMPK has beneficial effects in PAH animal models (Chandra et al, 2011;Yang et al, 2014). Taken (Yang, Read, et al, 2017).…”

Section: Discussionmentioning

confidence: 67%

“…Importantly, eNOS functions beyond generating a vasodilator, as eNOS gene transfer restored the microvascular loss in the MCT model (Zhao et al, 2006). AMPK mediated the pro-angiogenic effects of apelin and activation of AMPK has beneficial effects in PAH animal models (Chandra et al, 2011;Yang et al, 2014). We have found that MM07 could increase the phosphorylation of AMPKa in endothelial cells.…”

Section: Discussionmentioning

confidence: 83%

“…Apelin signalling is known to regulate endothelial NOS (eNOS), a critical enzyme that is thought to be protective in PAH and AMP-activated protein kinase (AMPK), a regulator of energy metabolism and angiogenesis (Chandra et al, 2011;Yang et al, 2014). We have tested whether MM07 could modulate these two targets.…”

Section: Regulation Of Pulmonary Arterial Endothelial Cell Signallingmentioning

confidence: 99%

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A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension

Yang

Read

Kuc

et al. 2019

British J Pharmacology

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Background and Purpose Apelin is an endogenous vasodilatory and inotropic peptide that is down‐regulated in human pulmonary arterial hypertension, although the density of the apelin receptor is not significantly attenuated. We hypothesised that a G protein‐biased apelin analogue MM07, which is more stable than the endogenous apelin peptide, may be beneficial in this condition with the advantage of reduced β‐arrestin‐mediated receptor internalisation with chronic use. Experimental Approach Male Sprague–Dawley rats received either monocrotaline to induce pulmonary arterial hypertension or saline and then daily i.p. injections of either MM07 or saline for 21 days. The extent of disease was assessed by right ventricular catheterisation, cardiac MRI, and histological analysis of the pulmonary vasculature. The effect of MM07 on signalling, proliferation, and apoptosis of human pulmonary artery endothelial cells was investigated. Key Results MM07 significantly reduced the elevation of right ventricular systolic pressure and hypertrophy induced by monocrotaline. Monocrotaline‐induced changes in cardiac structure and function, including right ventricular end‐systolic and end‐diastolic volumes, ejection fraction, and left ventricular end‐diastolic volume, were attenuated by MM07. MM07 also significantly reduced monocrotaline‐induced muscularisation of small pulmonary blood vessels. MM07 stimulated endothelial NOS phosphorylation and expression, promoted proliferation, and attenuated apoptosis of human pulmonary arterial endothelial cells in vitro. Conclusion and Implications Our findings suggest that chronic treatment with MM07 is beneficial in this animal model of pulmonary arterial hypertension by addressing disease aetiology. These data support the development of G protein‐biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 83%

Section: Regulation Of Pulmonary Arterial Endothelial Cell Signallingmentioning

confidence: 99%

See 1 more Smart Citation

A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension

Yang

Read

Kuc

et al. 2019

British J Pharmacology

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“…In addition, apelin promotes angiogenesis by activating AMPK activation in myocardial microvascular endothelial cells (Yang et al . ) and apelin is known to stimulate vasculogenesis in the placenta (Kurowska et al . ).…”

Section: Discussionmentioning

confidence: 99%

Exercise prevents the adverse effects of maternal obesity on placental vascularization and fetal growth

Son

Liu

Tian

et al. 2019

The Journal of Physiology

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Key pointsr Maternal exercise improves the metabolic health of maternal mice challenged with a high-fat diet.r Exercise intervention of obese mothers prevents fetal overgrowth. r Exercise intervention reverses impaired placental vascularization in obese mice. r Maternal exercise activates placental AMP-activated protein kinase, which was inhibited as a result of maternal obesity.Abstract More than one-third of pregnant women in the USA are obese and maternal obesity (MO) negatively affects fetal development, which predisposes offspring to metabolic diseases. The placenta mediates nutrient delivery to fetuses and its function is impaired as a result of MO. Exercise ameliorates metabolic dysfunction resulting from obesity, although its effect on placental function of obese mothers has not been explored. In the present study, C57BL/6J female mice were randomly assigned into two groups fed either a control or a high-fat diet (HFD) and then the mice on each diet were further divided into two subgroups with/without exercise. In HFD-induced obese mice, daily treadmill exercise during pregnancy reduced body weight gain, lowered serum glucose and lipid concentration, and improved insulin sensitivity of maternal mice. Importantly, maternal exercise prevented fetal overgrowth (macrosomia) induced by MO. To further examine the preventive effects of exercise on fetal overgrowth, placental vascularization and nutrient transporters were analysed. Vascular density and the expression of vasculogenic factors were reduced as a result of MO but were recovered by maternal exercise. On the other hand, the contents of nutrient transporters were not substantially altered by MO or exercise, suggesting that the protective effects of exercise in MO-induced fetal overgrowth were primarily a result of the alteration of placental vascularization and improved maternal metabolism. Furthermore, exercise enhanced downstream insulin signalling and activated AMP-activated protein kinase in HFD placenta. In sum, maternal exercise prevented fetal overgrowth induced by MO, which was Jun Seok Son received MS Degree in Kinesiology from Seoul National University. Currently, Jun Seok is a PhD student in the . His research interests focus on the impacts of maternal obesity, exercise, nutrition and other physiological conditions on fetal development and offspring health, especially the epigenetic mechanisms linking nutrients/metabolites to progenitor cell differentiation into myocytes/adipocytes. Ultimately, he aims to translate his work into clinical practice with respect to improving health outcomes for mothers and children affected by obesity.

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“…Considering these findings, the present study used late EPCs to assess angiogenesis under treatment with Tβ4. It was demonstrated that the Akt/eNOS pathway is a critical component in regulating the signaling of multiple biological processes (22,23). Through the activation of this pathway, the migration and anti-apoptotic ability of late EPCs increased, and finally promoted angiogenesis to aid ischemic myocardial survival.…”

Section: Discussionmentioning

confidence: 99%

Thymosin β4 promotes endothelial progenitor cell angiogenesis via a vascular endothelial growth factor‑dependent mechanism

Zhao

Song

et al. 2018

Mol Med Report

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Endothelial progenitor cells (EPCs) are a promising cell source for tissue repair and regeneration, predominantly through angiogenesis promotion. Paracrine functions serve a pivotal role in EPC‑mediated angiogenesis, which may be impaired by various cardiovascular risk factors. Therefore, it is important to identify a solution that optimizes the paracrine function of EPCs. Thymosin β4 (Tβ4) is a peptide with the potential to promote tissue regeneration and wound healing. A previous study demonstrated that Tβ4 enhances the EPC‑mediated angiogenesis of the ischemic myocardium. In the present study, whether Tβ4 improved angiogenesis by enhancing the paracrine effects of EPCs was investigated. A tube formation assay was used to assess the effect of angiogenesis, and the paracrine effects were measured using an ELISA kit. The results indicated that Tβ4 improved the paracrine effects of EPCs, evidenced by an increase in the expression of vascular endothelial growth factor (VEGF). EPC‑conditioned medium (EPC‑CM) significantly promoted human umbilical vein endothelial cell angiogenesis in vitro, which was further enhanced by pretreatment with Tβ4. The effect of Tβ4 pretreated EPC‑CM on angiogenesis was abolished by VEGF neutralizing antibody in vitro, indicating that increased VEGF secretion had a pivotal role in Tβ4‑mediated EPC angiogenesis. Furthermore, transplantation of EPCs pretreated with Tβ4 into infarcted rat hearts resulted in significantly higher VEGF expression in the border zone, compared with EPC transplantation alone. To further investigate whether the Akt/eNOS pathway was involved in Tβ4‑induced VEGF secretion in EPCs, the expression levels of VEGF in EPC‑CM were significantly decreased following knockdown of Akt or eNOS by small interfering RNA transfection. In conclusion, Tβ4 significantly increased angiogenesis by enhancing the paracrine effects of EPCs, evidenced by the increased expression of VEGF. The RAC‑α serine/threonine‑protein kinase/endothelial nitric oxide synthase signal transduction pathway was involved in the regulation of Tβ4‑induced VEGF secretion in EPCs. Further studies are required to investigate the long‑term prognosis of patients with coronary heart disease following Tβ4‑pretreated EPC transplantation.

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

Cited by 33 publications

References 32 publications

A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension

A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension

Exercise prevents the adverse effects of maternal obesity on placental vascularization and fetal growth

Thymosin β4 promotes endothelial progenitor cell angiogenesis via a vascular endothelial growth factor‑dependent mechanism

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