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Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1.

ABSTRACT: Coronary artery anomalies may cause life-threatening cardiac complications; however, developmental mechanisms underpinning coronary artery formation remain ill-defined. Here we identify an angiogenic cell population for coronary artery formation in mice. Regulated by a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis, these angiogenic cells generate mature coronary arteries. The NOTCH modulator POFUT1 critically regulates this signaling axis. POFUT1 inactivation disrupts signaling events and results in excessive angiogenic cell proliferation and plexus formation, leading to anomalous coronary arteries, myocardial infarction and heart failure. Simultaneous VEGFR2 inactivation fully rescues these defects. These findings show that dysregulated angiogenic precursors link coronary anomalies to ischemic heart disease.Though coronary arteries are crucial for heart function, the mechanisms guiding their formation are largely unknown. Here, Wang et al. identify a unique, endocardially-derived angiogenic precursor cell population for coronary artery formation in mice and show that a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis is key for coronary artery development.

SUBMITTER: Wang Y

PROVIDER: S-EPMC5603578 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1.

Wang Yidong Y Wu Bingruo B Lu Pengfei P Zhang Donghong D Wu Brian B Varshney Shweta S Del Monte-Nieto Gonzalo G Zhuang Zhenwu Z Charafeddine Rabab R Kramer Adam H AH Sibinga Nicolas E NE Frangogiannis Nikolaos G NG Kitsis Richard N RN Adams Ralf H RH Alitalo Kari K Sharp David J DJ Harvey Richard P RP Stanley Pamela P Zhou Bin B

Nature communications 20170918 1

Coronary artery anomalies may cause life-threatening cardiac complications; however, developmental mechanisms underpinning coronary artery formation remain ill-defined. Here we identify an angiogenic cell population for coronary artery formation in mice. Regulated by a DLL4/NOTCH1/VEGFA/VEGFR2 signaling axis, these angiogenic cells generate mature coronary arteries. The NOTCH modulator POFUT1 critically regulates this signaling axis. POFUT1 inactivation disrupts signaling events and results in e ...[more]

PMID: 28924218

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Project description:Cardiovascular disease (CVD) is the most prominent cause of death of adults in the United States with coronary artery disease being the most common type of CVD. Following a myocardial event, the coronary endothelium plays an important role in the recovery of the ischemic myocardium. Specifically, endothelial cells (EC) must be able to elicit a robust angiogenic response necessary for tissue revascularization and repair. However, local or distant cues may prevent effective revascularization. Extracellular vesicles (EV) are produced by all cells and endothelium is a rich source of EVs that have access to the main circulation thereby potentially impacting local and distant tissue function. Systemic inflammation associated with conditions such as obesity as well as the acute inflammatory response elicited by a cardiac event can significantly increase the EV release by endothelium and alter their miRNA, protein or lipid cargo. Our laboratory has previously shown that EVs released by adipose tissue endothelial cells exposed to chronic inflammation have angiostatic effects on naïve adipose tissue EC in vitro. Whether the observed effect is specific to EVs from adipose tissue endothelium or is a more general feature of the endothelial EVs exposed to pro-inflammatory cues is currently unclear. The objective of this study was to investigate the angiostatic effects of EVs produced by EC from the coronary artery and adipose microvasculature exposed to pro-inflammatory cytokines (PIC) on naïve coronary artery EC. We have found that EVs from both EC sources have angiostatic effects on the coronary endothelium. EVs produced by cells in a pro-inflammatory environment reduced proliferation and barrier function of EC without impacting cellular senescence. Some of these functional effects could be attributed to the miRNA cargo of EVs. Several miRNAs such as miR-451, let-7, or miR-23a impact on multiple pathways responsible for proliferation, cellular permeability and angiogenesis. Collectively, our data suggests that EVs may compete with pro-angiogenic cues in the ischemic myocardium therefore slowing down the repair response. Acute treatments with inhibitors that prevent endogenous EV release immediately after an ischemic event may contribute to better efficacy of therapeutic approaches using functionalized exogenous EVs or other pro-angiogenic approaches.

Project description:BackgroundCoronary magnetic resonance angiography (CMRA) is being increasingly used in pediatric patients with congenital coronary artery anomalies (CAAs). However, the data on the free-breathing self-navigation technique, which has the potential to simplify the acquisition plan with a high success rate at 3T, remain scarce. This study investigated the clinical application value of self-navigated (sNAV) CMRA at 3T in pediatric patients with suspected CAAs and compared it to conventional diaphragmatic-navigated (dNAV) CMRA.MethodsFrom April 2019 to March 2022, we enrolled 65 pediatric patients (38 males and 27 females; mean age 8.5±4.4 years) with suspected CAAs in this prospective study. All patients underwent both dNAV and sNAV sequences in random order with gradient recalled echo (GRE) sequence during free breathing, with 39 (20 males and 19 females; mean age 10.2±3.6 years) of them additionally undergoing coronary computed tomography angiography (CCTA) or invasive coronary angiography (ICA). We measured and compared the success rate, scan time, visual score of the 9 main coronary artery segments, vessel sharpness, and vessel length between the two sequences. The diagnostic accuracy was compared using CCTA or ICA as a reference.ResultsThe success rate of sNAV-CMRA (65/65, 100%) was higher than that of dNAV-CMRA (61/65, 93.8%) (P<0.001), and the scan time of sNAV-CMRA (7.3±2.5 min) was significantly shorter than that of dNAV-CMRA (9.1±3.6 min) (P=0.002). The acquisition efficiency of dNAV-CMRA was 40.5%±12.9%, while for sNAV-CMRA, 100% acquisition efficiency was achieved. There was no significant difference in vessel length of any of the coronary arteries, visual score, or vessel sharpness of the left circumflex coronary artery (LCX) between the two sequences (all P values >0.050). The visual score and vessel sharpness of the right coronary artery and left anterior descending coronary artery (LAD) were significantly improved in dNAV-CMRA compared with sNAV-CMRA (all P values <0.050). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the detection of CAAs were not significantly different between the two sequences (all P values >0.050).ConclusionsOur findings demonstrated that both sNAV and dNAV in CMRA provide clinical application value in pediatric patients with CAAs and have similar diagnostic performance. Although the image quality of sNAV-CMRA is slightly inferior compared to that of dNAV-CMRA, sNAV-CMRA allows for a simpler scanning procedure.

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Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1.

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Uncontrolled angiogenic precursor expansion causes coronary artery anomalies in mice lacking Pofut1.

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