Gastrin mediates cardioprotection through angiogenesis after myocardial infarction by activating the HIF-1α/VEGF signalling pathway.
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ABSTRACT:
SUBMITTER: Wang R
PROVIDER: S-EPMC8339006 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Myocardial infarction (MI) is a severe disease that often associated with dysfunction of angiogenesis. Cell-based therapies for MI using mesenchymal stem cell (MSC)-derived exosomes have been well studied due to their strong proangiogenic effect. Genetic modification is one of the most common methods to enhance exosome therapy. This study investigated the proangiogenic and cardioprotective effect of exosomes derived from hypoxia-inducible factor 1-alpha (HIF-1?)-modified MSCs. METHODS:Lentivirus containing HIF-1? overexpressing vector was packaged and used to infect MSCs. Exosomes were isolated from MSC-conditioned medium by ultracentrifugation. Human umbilical vein endothelial cells (HUVECs) were treated under hypoxia condition for 48?h co-cultured with PBS, control exosomes, or HIF-1?-overexpressed exosomes, respectively. Then the preconditioned HUVECs were subjected to tube formation assay, Transwell assay, and EdU assay to evaluate the protective effect of exosomes. Meanwhile, mRNA and secretion levels of proangiogenic factors were measured by RT-qPCR and ELISA assays. In vivo assays were conducted using the rat myocardial infarction model. PBS, control exosomes, or HIF-1?-overexpressed exosomes were injected through tail vein after MI surgery. Heart function was assessed by echocardiography at days 3, 14, and 28. At day 7, mRNA and protein expression levels of proangiogenic factors in the peri-infarction area and circulation were evaluated, respectively. At day 28, hearts were collected and subjected to H&E staining, Masson's trichrome staining, and immunofluorescent staining. RESULTS:HIF-1?-overexpressed exosomes rescued the impaired angiogenic ability, migratory function, and proliferation of hypoxia-injured HUVECs. Simultaneously, HIF-1?-overexpressed exosomes preserved heart function by promoting neovessel formation and inhibiting fibrosis in the rat MI model. In addition, both in vitro and in vivo proangiogenic factors mRNA and protein expression levels were elevated after HIF-1?-overexpressed exosome application. CONCLUSION:HIF-1?-overexpressed exosomes could rescue the impaired angiogenic ability, migration, and proliferation of hypoxia-pretreated HUVECs in vitro and mediate cardioprotection by upregulating proangiogenic factors and enhancing neovessel formation.
| S-EPMC7455909 | biostudies-literature
Project description:Exercise training is believed to have a positive effect on cardiac hypertrophy after hypertension. However, its mechanism is still not fully understood. Herein, our findings suggest that heat shock transcription factor 1 (HSF1) improves exercise-initiated myocardial angiogenesis after pressure overload. A sustained narrowing of the diagonal aorta (TAC) and moderately- intense exercise training protocol were imposed on HSF1 heterozygote (KO) and their littermate wild-type (WT) male mice. After two months, the cardiac function was assessed using the adaptive responses to exercise training, or TAC, or both of them such as catheterization and echocardiography. The HE stains assessed the area of myocyte cross-sectional. The Western blot and real-time PCR measured the levels of expression for heat shock factor 1 (HSF1), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1α) in cardiac tissues. The anti-CD31 antibody immunohistochemical staining was done to examine how exercise training influenced cardiac ontogeny. The outcome illustrated that exercise training significantly improved the cardiac ontogeny in TAC mice, which was convoyed by elevated levels of expression for VEGF and HIF-1α and preserved the heart microvascular density. More importantly, HSF1 deficiency impaired these effects induced by exercise training in TAC mice. In conclusion, exercise training encourages cardiac ontogeny by means of HSF1 activation and successive HIF-1α/VEGF up-regulation in endothelial cells during continued pressure overload.
| S-EPMC7011135 | biostudies-literature
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.
| S-EPMC6291966 | biostudies-literature
Project description:Hypoxic pulmonary hypertension (HPH) lacks effective pharmacologic treatments. Microarray-based gene expression indicates the crucial role of Cullin 5 (Cul 5) in HPH. This study showed that Cul 5 was upregulated in HPH patients and a murine model of HPH. In vitro, Cul 5 promoted the angiogenesis and adhesion capacity of human pulmonary artery endothelial cells (PAECs), which could be mitigated by Cul 5 inactivation mediated by pevonedistat or NEDD8 silence. In vivo, silencing of Cul 5 in the endothelium and Cul 5 inactivation by pevonedistat could also alleviate hypoxic vascular remodeling. Mechanistic research showed that Cul 5 participated in HPH pathogenesis via the TRAF6/NF-κB/HIF-1α/VEGF pathway. Inhibition of the TRAF6/NF-κB/HIF-1α/VEGF pathway could reverse Cul 5-induced human PAEC dysfunction. These findings demonstrate that Cul 5 is an important mediator of HPH via the TRAF6/NF-κB/HIF-1α/VEGF pathway firstly, and could be considered as a potential therapeutic target in the clinical treatment of HPH.
| S-EPMC10641258 | biostudies-literature
Project description:In this paper, a curcumin derivative Cur20 was synthesized for better hydrolytic stability, which showed a higher angiogenic effect on zebrafish model than curcumin. In order to reveal the potential effects on neuroprotection, a mouse model of vascular dementia (VaD) induced by permanent right common carotid artery occlusion (rUCCAO) was established. After two weeks of curcumin administration, the cognitive function of mice was detected by Morris water maze and Y maze. The alteration on oxidative injuries and morphological damage were also analyzed by reactive oxygen species, superoxide dismutase, GSH, malondialdehyde tests, and Nissl stain on cortex/hippocampus. The angiogenesis and related signal factors were evaluated as well. The results showed that Cur20 significantly attenuated the cognitive dysfunction and histopathological changes of the VaD mice with enhanced antioxidant system and angiogenesis. In addition, primary rat brain microvessel endothelial cells (rBMECs) with oxygen glucose deprivation (OGD) were applied to further verify the possible mechanisms of Cur20-induced angiogenesis. The results demonstrated that the proliferation effect and the activation of pro-angiogenesis factors such as HIF-1α, VEGF, and TFEB might contribute to the protection of ischemic injury. Based on the above, our conclusion is that Cur20 can be considered as a promising therapeutic strategy for VaD.
| S-EPMC8082391 | biostudies-literature
Project description: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)-1α 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.
| S-EPMC5459903 | biostudies-literature
Project description:BackgroundAngiogenesis is considered as an important process in the development of malignancies and is associated with cancer progression and metastasis. Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and is recognized as a typical angiogenic tumor. Thus, it is of great importance to study the underlying mechanism of angiogenesis in HCC. The long non-coding RNA (lncRNA) ubiquitin conjugating enzyme E2C pseudogene 3 (UBE2CP3) has been reported as an oncogene that promotes tumor metastasis in HCC. However, the role and underlying mechanisms of UBE2CP3 in HCC angiogenesis are still unclear.MethodsWe measured the expression levels of UBE2CP3 by in situ hybridization (ISH) and quantitative real-time polymerase chain reaction (qRT-PCR) in HCC patient samples. We also concomitantly used CD31/PAS double-staining to measure endothelial vessel (EV) density and used qRT-PCR to measure the CD31 mRNA level. HepG2 and SMMC-7721 cells were transfected with Lv-UBE2CP3 or Sh-UBE2CP3 virus to obtain stably over-expressing or knocking-down UBE2CP3 cell lines. The indirect effects of UBE2CP3 on ECs were studied by establishing a co-culture system using Transwell chambers with a 0.4-μm pore size. HCC cells and ECs in the co-culture system were separated, but the cytokines and growth factors were able to communicate with each other. Following exposed to HCC cells, ECs were collected for functional studies. Finally, we studied the function of UBE2CP3 in vivo by chick embryo chorioallantoic membrane (CAM) angiogenesis assays and nude mouse tumorigenicity assays.ResultsIn this study, we found that UBE2CP3 expression was higher in HCC tissues than in para-tumor tissues and was up-regulated in tissues with high EV density. Functionally, we found that in the co-culture systems, HCC cells overexpressing UBE2CP3 promoted HUVEC proliferation, migration and tube formation via the activation of ERK/HIF-1α/p70S6K/VEGFA signalling, increasing the level of VEGFA in HCC cell supernatant. In addition, the opposite results appeared when the expression of UBE2CP3 in HCC cells was knocked down. Consistent with these results, CAM angiogenesis assays and nude mouse tumorigenicity assays showed that UBE2CP3 expression up-regulated EV density in vivo.ConclusionOur study suggests that UBE2CP3 can enhance the interaction between HCC tumor cells and HUVECs and promote HCC tumorigenicity by facilitating angiogenesis.
| S-EPMC5987644 | biostudies-literature
Project description:Vascular endothelial growth factor (VEGF) is a well-known angiogenic factor, however its ability in promoting therapeutic angiogenesis following myocardial infarction (MI) is limited. Here, we aimed to investigate whether dual treatment with insulin-like growth factor binding protein-4 (IGFBP-4), an agent that protects against early oxidative damage, can be effective in enhancing the therapeutic effect of VEGF following MI. Combined treatment with IGFBP-4 enhanced VEGF-induced angiogenesis and prevented cell damage via enhancing the expression of a key angiogenic factor angiopoietin-1. Dual treatment with the two agents synergistically decreased cardiac fibrosis markers collagen-I and collagen-III following MI. Importantly, while the protective action of IGFBP-4 occurs at an early stage of ischemic injury, the action of VEGF occurs at a later stage, at the onset angiogenesis. Our findings demonstrate that VEGF treatment alone is often not enough to protect against oxidative stress and promote post-ischemic angiogenesis, whereas the combined treatment with IGFBP4 and VEGF can utilize the dual roles of these agents to effectively protect against ischemic and oxidative injury, and promote angiogenesis. These findings provide important insights into the roles of these agents in the clinical setting, and suggest new strategies in the treatment of ischemic heart disease.
| S-EPMC7417680 | biostudies-literature
Project description:Hypoxia is a condition of decreased availability of oxygen. When cells are exposed to a low oxygen environment, they impel the hypoxia responses to adapt to new situation. The hypoxia response leads to the activation of various cellular signaling pathways. The aim of this study was to evaluate the effect of ghrelin on angiogenesis, Hypoxia-Inducible-Factor-1α (HIF-1) and Vascular endothelial growth factor (VEGF) levels in normobaric hypoxia situation.Twenty four animals were divided into 4 groups (n=6): control (C), ghrelin (Gh), hypoxia (H), and hypoxic animals that received ghrelin (H+Gh). Hypoxia (11%) was induced by an Environmental Chamber System GO2 Altitude. Animals in ghrelin groups received a subcutaneous injection of ghrelin (150 μg/kg/day) for 14 days.Our results showed that hypoxia significantly (p<0.05) increased angiogenesis without any significant changes on HIF-1 and VEGF levels, whereas ghrelin significantly (p<0.05) decreased angiogenesis, expression of HIF-1 and VEGF in this condition. Ghrelin administration did not show any significant changes in normal conditions.Ghrelin had no effect on angiogenesis, expression of HIF-1 and VEGF in normal oxygen conditions but it reduced angiogenesis process in lung tissue with reducing the level of HIF and VEGF in hypoxic condition. Therefore, effect of ghrelin on angiogenesis could be related to blood oxygen level.
| S-EPMC4616885 | biostudies-other
Project description:The current study aimed to explore the role of tumor-derived extracellular vesicles (EVs) in angiogenesis during nasopharyngeal carcinoma (NPC). NPC biopsy specimens were initially collected. Human umbilical vein endothelial cells (HUVECs) were co-cultured with EVs isolated from NPC cells, after which their migration, invasion, as well as vessel-like tube formation were evaluated by Transwell chamber systems and Matrigel-based angiogenesis assays. The pro-angiogenic activities of EVs as well as the candidate microRNA (miRNA or miR) were examined using an in vivo Matrigel angiogenesis model. The results indicated that the levels of miR-144 in the NPC tissues were upregulated when compared to the nasopharyngeal normal tissues in addition to the identification of a positive correlation with the expression of CD31. Moreover, our data indicated that miR-144 was highly enriched in EVs from NPC cells and then ultimately enhanced the migration and invasion of HUVECs and vessel-like tubes in vitro and in vivo. Notably, miR-144 was identified as a mediator in NPC-EV-induced regulatory effects through the inhibition of the target gene FBXW7 and promotion of the transcriptional factor HIF-1α-dependent vascular endothelial growth factor (VEGF-A). Taken together, the key findings of the current study highlighted the role of miR-144 as an extracellular pro-angiogenic mediator in NPC tumorigenesis.
| S-EPMC8143977 | biostudies-literature