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Leonurine Improves Age-Dependent Impaired Angiogenesis: Possible Involvement of Mitochondrial Function and HIF-1? Dependent VEGF Activation.

ABSTRACT: Objective: Advanced age is associated with impaired angiogenesis in part because of mitochondrial dysfunction. We have recently reported that leonurine exerts protective effects in neuron via regulation of mitochondrial function. The aim of this study was to explore whether leonurine is able to attenuate mitochondrial dysfunction and to enhance angiogenesis in old rats with hindlimb ischemia. Methods and Results: At day 14 after surgery, hypoxia-inducible factor (HIF)-1? and vascular endothelial growth factor (VEGF) expression was decreased in the ischemic muscle of aged animals, which was accompanied by enhanced oxidative stress, increased mitochondrial damage, decreased capillary density, and reduced limb perfusion compared with young mice. Importantly, these effects were inhibited by leonurine treatment in old animals. In vitro, we showed that the functional activities (migration and tube formation) of human umbilical vein endothelial cells (HUVECs) were significantly impaired in senescent compared to young. However, leonurine rescued HUVECs functional activities in senescent HUVECs. Mechanistically, we found that leonurine restored the age-dependent reduction in HIF activity and subsequent reduced VEGF expression in senescent HUVECs. Moreover, the mitochondrial oxidative stress was significantly augmented in senescent HUVECs, in association with reduced mitochondrial function. However, leonurine significantly reduced the mitochondrial oxidative stress and restored the mitochondrial membrane potential. Conclusion: Our results demonstrate that leonurine protects against age-dependent impairment of angiogenesis possibly through attenuation of mitochondrial dysfunction and subsequent VEGF up-regulation impairment.

SUBMITTER: Qi J

PROVIDER: S-EPMC5459903 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Leonurine Improves Age-Dependent Impaired Angiogenesis: Possible Involvement of Mitochondrial Function and HIF-1α Dependent VEGF Activation.

Qi Jia J Wang Jing J JJ Duan Jun L JL Lu Zhao Y ZY Yuan Yang G YG

Frontiers in pharmacology 20170606

<b>Objective:</b> Advanced age is associated with impaired angiogenesis in part because of mitochondrial dysfunction. We have recently reported that leonurine exerts protective effects in neuron via regulation of mitochondrial function. The aim of this study was to explore whether leonurine is able to attenuate mitochondrial dysfunction and to enhance angiogenesis in old rats with hindlimb ischemia. <b>Methods and Results:</b> At day 14 after surgery, hypoxia-inducible factor (HIF)-1α and vascul ...[more]

PMID: 28634450

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Project description:BackgroundAldehyde dehydrogenase 1A1 (ALDH1A1), a member of aldehyde dehydrogenase family, is a marker of stemness in breast cancer. During tumor progression cancer stem cells (CSCs) have been reported to secrete angiogenic factors to orchestrate the formation of pathological angiogenesis. This vasculature can represent the source of self-renewal of CSCs and the route for further tumor spreading. The aim of the present study has been to assess whether ALDH1A1 controls the output of angiogenic factors in breast cancer cells and regulates tumor angiogenesis in a panel of in vitro and in vivo models.MethodsStemness status of breast cancer cells was evaluated by the ability to form turmorspheres in vitro. A transwell system was used to assess the angiogenic features of human umbilical vein endothelial cells (HUVEC) when co-cultured with breast cancer cells MCF-7 harboring different levels of ALDH1A1. Under these conditions, we survey endothelial proliferation, migration, tube formation and permeability. Moreover, in vivo, MCF-7 xenografts in immunodeficient mice allow to evaluate blood flow, expression of angiogenic factors and microvascular density (MVD).ResultsIn MCF-7 we observed that ALDH1A1 activity conferred stemness property and its expression correlated with an activation of angiogenic factors. In particular we observed a significant upregulation of hypoxia inducible factor-1α (HIF-1α) and proangiogenic factors, such as vascular endothelial growth factor (VEGF). High levels of ALDH1A1, through the retinoic acid pathway, were significantly associated with VEGF-mediated angiogenesis in vitro. Co-culture of HUVEC with ALDH1A1 expressing tumor cells promoted endothelial proliferation, migration, tube formation and permeability. Conversely, downregulation of ALDH1A1 in MCF-7 resulted in reduction of proangiogenic factor release/expression and impaired HUVEC angiogenic functions. In vivo, when subcutaneously implanted in immunodeficient mice, ALDH1A1 overexpressing breast tumor cells displayed a higher expression of VEGF and MVD.ConclusionIn breast tumors, ALDH1A1 expression primes a permissive microenvironment by promoting tumor angiogenesis via retinoic acid dependent mechanism. In conclusion, ALDH1A1 might be associated to progression and diffusion of breast cancer.

Dataset Information

Leonurine Improves Age-Dependent Impaired Angiogenesis: Possible Involvement of Mitochondrial Function and HIF-1? Dependent VEGF Activation.

Publications

Leonurine Improves Age-Dependent Impaired Angiogenesis: Possible Involvement of Mitochondrial Function and HIF-1α Dependent VEGF Activation.

Similar Datasets

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