Wnt/β-catenin coupled with HIF-1α/VEGF signaling pathways involved in galangin neurovascular unit protection from focal cerebral ischemia

Wu, Chun‐Ming; Chen, Jianxin; Chen, Chang; Wang, Wei; Wen, Limei; Gao, Kuo; Chen, Xiuping; Xiong, Sihuai; Zhao, Huihui; Li, Shaojing

doi:10.1038/srep16151

Cited by 83 publications

(63 citation statements)

References 57 publications

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“…During homeostasis, endothelial Fzd4 deletion produces BBB compromise in adult mice 12 , whereas conditional deletion of endothelial Ctnnb1 in adult mice induces BBB breakdown and brain petechial hemorrhage, either through transcriptional activation or the adherens-junction functions of β-catenin 24 . During pathologic conditions, Wnt–β-catenin signaling in unfractionated brain tissue is correlated with tissue damage and hemorrhagic transformation after ischemic stroke 25,26 , and endothelial Wnt–β-catenin signaling is functionally implicated in the regulation of vascular integrity in glioblastoma 27 .…”

mentioning

confidence: 99%

Gpr124 is essential for blood–brain barrier integrity in central nervous system disease

Chang¹,

Mancuso²,

Maier³

et al. 2017

Nat Med

196

190

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Although blood–brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt–β-catenin signaling. Constitutive activation of Wnt–β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.

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mentioning

confidence: 99%

Gpr124 is essential for blood–brain barrier integrity in central nervous system disease

Chang¹,

Mancuso²,

Maier³

et al. 2017

Nat Med

196

190

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show abstract

“…It has been suggested that Wnt signaling regulates VEGF, or vice versa, to control angiogenesis 43–45 . It is possible that Wnt/β-catenin signaling is required for, or synergistically regulates, HIFα-activated VEGFA expression.…”

Section: Discussionmentioning

confidence: 99%

Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways

Zhang

Zhu

Gui

et al. 2020

Preprint

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AbstractThe mechanisms by which oligodendroglia modulate CNS angiogenesis remain elusive. Previous in vitro data suggest that oligodendroglia regulate CNS endothelial cell proliferation and blood vessel formation through hypoxia inducible factor alpha (HIFα)-activated Wnt (but not VEGF) signaling. Using in vivo genetic models, we show that HIFα in oligodendroglia is necessary and sufficient for angiogenesis independent of CNS regions. At the molecular level, HIFα stabilization in oligodendroglia does not perturb Wnt signaling but remarkably activates VEGF. At the functional level, genetically blocking oligodendroglia-derived VEGF but not Wnt significantly decreases oligodendroglial HIFα-regulated CNS angiogenesis. Interestingly, blocking astroglia-derived Wnt signaling reduces astroglial HIFα-regulated CNS angiogenesis. Together, our in vivo data clearly demonstrate that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling. Our findings represent an alternative mechanistic understanding of CNS angiogenesis by postnatal glial cells and unveil a glial cell type-dependent HIFα-Wnt axis in regulating CNS vessel formation.

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“…β‐catenin is excessively expressed in many cancer cells. Usually, β‐catenin contributes to cytoskeletal maintenance in co‐operation with actin, and the intracytoplasmic β‐catenin is controlled at a low level by proteasome‐dependent proteolysis controlled by a complex including axin, adenomatous polyposis coli (APC), glycogen synthase kinase‐3b (GSK‐3b), and casein kinase 1a (CK1a) (Wu et al., ). However, in many cancer cells, the degradation of β‐catenin is inhibited and β‐catenin is accumulated in the cytoplasm by an extracellular secretory glycoprotein called Wnt, which binds to the complex of Frizzled (Fz) and the low‐density lipoprotein receptor‐related protein (LRP) (Duchartre, Kim, & Kahn, ).…”

Section: Discussionmentioning

confidence: 99%

Antitumor effect of palmitic acid‐conjugated DsiRNAfor colon cancer in a mouse subcutaneous tumor model

et al. 2019

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In this study, we synthesized Dicer‐substrate siRNA conjugated with palmitic acid at the 5′‐end of the sense strand (C16‐DsiRNA), and examined its RNAi effect on β‐catenin as a target gene in a colon cancer cell line, HT29Luc, both in vitro and in vivo. We examined the in vitro RNAi effect in HT29Luc cells and found that C16‐DsiRNA strongly inhibited expression of the β‐catenin gene in comparison with non‐modified DsiRNA. Also, high membrane permeability of C16‐DsiRNA was exhibited, and it was confirmed that most of the C16‐DsiRNA was localized in cytoplasm of HT29Luc cells. In regard to the in vivo RNAi effect, C16‐DsiRNA complexed with Invivofectamine targeting the β‐catenin gene was locally administered to a subcutaneous tumor formed by implantation of HT29Luc cells into the subcutis of nude mice; we evaluated the effect by measuring the bioluminescence increase, which reflects tumor growth, using an in vivo imaging system. As a result, C16‐DsiRNA strongly inhibited the growth of tumors formed in subcutis of nude mice compared with non‐modified DsiRNA, and this in vivo RNAi effect lasted up to 15 days. Our results suggest that C16‐DsiRNA should be vigorously pursued as a novel nucleic acid medicine for clinical treatment of cancer.

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Wnt/β-catenin coupled with HIF-1α/VEGF signaling pathways involved in galangin neurovascular unit protection from focal cerebral ischemia

Cited by 83 publications

References 57 publications

Gpr124 is essential for blood–brain barrier integrity in central nervous system disease

Gpr124 is essential for blood–brain barrier integrity in central nervous system disease

Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways

Antitumor effect of palmitic acid‐conjugated DsiRNAfor colon cancer in a mouse subcutaneous tumor model

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