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

Wang, Yidong; Wu, Bingruo; Lu, Pengfei; Zhang, Donghong; Wu, Brian Bo-Chang; Varshney, Shweta; Monte‐Nieto, Gonzalo del; Zhuang, Zhenwu; Charafeddine, Rabab A.; Kramer, Adam H.; Sibinga, Nicholas E.S.; Frangogiannis, Nikolaos G.; Kitsis, Richard N.; Adams, Ralf H.; Alitalo, Kari; Sharp, David J.; Harvey, Richard P.; Stanley, Pamela; Zhou, Bin

doi:10.1038/s41467-017-00654-w

Cited by 37 publications

(29 citation statements)

References 66 publications

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“…After the treatment of MPO, the gene expression of Vegfa, Vegfr2 were significantly increased comparing with CP or Meg3 group. Great deals of researches [29,30] have demonstrated that the increased Vegfa, Vegfr2 were crucial processes in angiogenesis [31][32][33]. We could get similar results in western blotting experiment.…”

Section: Mpo Up-regulated Vegfa and Vegfr2 Expressionsupporting

confidence: 62%

Fabrication of a nano polymer wrapping Meg3 ShRNA plasmid for the treatment of cerebral infarction

Shen

Zhao

Wang

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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Cerebral infarction is with poorer prognosis and high rates of mortality. After cerebral infarction, the promoting angiogenesis can accelerate the recovery of neurological function. Long non-coding RNA (LncRNA) maternally expressed gene 3 (Meg3) was overexpressed in cerebral infarction area and the knockdown of Meg3 promotes neovascularization and improves nerve function. In this study, we fabricated a nano-polymer wrapped Meg3 short hairpin RNA (ShRNA) plasmid to knockdown Meg3 and conjugated with OX26 antibody (MPO) to realize the brain targeting for the treatment of cerebral infarction. The MPO particle size was 103 ± 11 nm (PDI = 0.27) detected by dynamic light scattering (DLS) and the zeta potential of MPO was -32 mV. MPO achieved brain microvascular endothelial cell (BMEC) targeting and enhanced endothelial cells migration (p < .05), and tube formation (p < .05) in vitro. MPO realized brain tissue target, reduced the volume of cerebral infarction (p < .05) detected by TTC staining, increased capillary density through the HE staining and increased cerebral cortex micro-vessel through immunofluorescence method in vivo. The angiogenesis associated genes Vegfa, and Vegfr2 were upregulated after the treatment of MPO, compared with Meg3 or control plasmid treated group. This study suggested that MPO could achieve brain target and significantly promoted angiogenesis and became a new treatment method for cerebral infarction.

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Section: Mpo Up-regulated Vegfa and Vegfr2 Expressionsupporting

confidence: 62%

Fabrication of a nano polymer wrapping Meg3 ShRNA plasmid for the treatment of cerebral infarction

Shen

Zhao

Wang

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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“…A similar genetic signature and mechanism were identified in capillary pre-arterial ECs in developing mouse hearts by scRNAseq and genetic lineage tracing analysis [285]. Genetic deletion experiments in developing coronary vessels confirmed the importance of Dll4-Notch signaling for the formation of coronary arteries [286,287]. Collectively, these studies suggest that prearterial capillaries contain pre-determined endothelial cells, having an arterial signaling and genetic profile consisting of high VEGF/Notch/Cxcr4 activity that commits them to form arteries.…”

Section: Vascular Anomalies Caused By Abnormal Mitogenic Stimulationsupporting

confidence: 59%

Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology

Mühleder

Fernández-Chacón

García-González

et al. 2020

Cell. Mol. Life Sci.

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Therapeutic modulation of vascular cell proliferation and migration is essential for the effective inhibition of angiogenesis in cancer or its induction in cardiovascular disease. The general view is that an increase in vascular growth factor levels or mitogenic stimulation is beneficial for angiogenesis, since it leads to an increase in both endothelial proliferation and sprouting. However, several recent studies showed that an increase in mitogenic stimuli can also lead to the arrest of angiogenesis. This is due to the existence of intrinsic signaling feedback loops and cell cycle checkpoints that work in synchrony to maintain a balance between endothelial proliferation and sprouting. This balance is tightly and effectively regulated during tissue growth and is often deregulated or impaired in disease. Most therapeutic strategies used so far to promote vascular growth simply increase mitogenic stimuli, without taking into account its deleterious effects on this balance and on vascular cells. Here, we review the main findings on the mechanisms controlling physiological vascular sprouting, proliferation, and senescence and how those mechanisms are often deregulated in acquired or congenital cardiovascular disease leading to a diverse range of pathologies. We also discuss alternative approaches to increase the effectiveness of pro-angiogenic therapies in cardiovascular regenerative medicine.

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“…Input from other signaling pathways (Wnt), downstream effectors (Erk, PI3K), and transcription factors (ETS, Fox) were subsequently shown to modulate artery differentiation in concert with VEGF and Notch (Corada et al, 2010;Hong, Peterson, Hong, & Peterson, 2006;Neal et al, 2019;Seo et al, 2006;Sissaoui et al, 2020;Wythe et al, 2013;You et al, 2005). Recent work has confirmed that several of these pathways also control artery specification in the coronary vasculature (Travisano et al, 2019;Su et al, 2018;Wang et al, 2017;Wu et al, 2012).…”

Section: Discussionmentioning

confidence: 95%

“…An important feature of this transgenic model was that it displayed no gross defects in heart development or lethality. In contrast, genetic or pharmacological alterations in Notch or VEGF have strong effects on endothelial cell cycle and dramatically change the number of ECs in the heart (Fang et al, 2017;Pontes-Quero et al, 2019;Travisano et al, 2019;Wang et al, 2017;Wu et al, 2012). Thus, manipulation of Notch or VEGF make it difficult to conclude whether changes in artery growth are due to cell autonomous effects or secondary to dysregulated heart development.…”

Section: Discussionmentioning

confidence: 99%

Dach1 extends artery networks and protects against cardiac injury

Raftrey

Williams

Coronado

et al. 2020

Preprint

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Coronary artery disease (CAD) is the leading cause of death worldwide, but there are currently no available methods to stimulate growth or regeneration of artery networks in diseased hearts. Studying how arteries are built during embryonic development could illuminate strategies for re-building these vessels in the setting of ischemic heart disease. We previously found, using loss-of-function experiments, that the transcription factor Dach1 is required for coronary artery development in mouse embryos. Here, we report that Dach1 overexpression in endothelial cells (ECs) extended coronary arteries and improved survival and heart function in adult mice following myocardial infarction (MI). Dach1 overexpression increased the length and number of arterial end branches, in both heart and retinal vasculature, by causing additional capillary ECs to differentiate into arterial ECs and contribute to growing arteries. Single-cell RNA sequencing (scRNAseq) of ECs undergoing Dach1-induced arterial specification indicated that it potentiated normal artery differentiation, rather than functioning as a master regulator of artery cell fate. ScRNAseq also showed that normal arterial differentiation is accompanied by repression of lipid metabolism genes, which were also repressed by Dach1 prior to arterialization. Together, these results demonstrate that increasing the expression level of Dach1 is a novel pathway for driving specification of artery ECs and extending arterial vessels, which could be explored as a means of increasing artery coverage to mitigate the effects of CAD.

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

Cited by 37 publications

References 66 publications

Fabrication of a nano polymer wrapping Meg3 ShRNA plasmid for the treatment of cerebral infarction

Fabrication of a nano polymer wrapping Meg3 ShRNA plasmid for the treatment of cerebral infarction

Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology

Dach1 extends artery networks and protects against cardiac injury

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