Loss of endothelial glucocorticoid receptor promotes angiogenesis via upregulation of Wnt/β-catenin pathway,Angiogenesis

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Loss of endothelial glucocorticoid receptor promotes angiogenesis via upregulation of Wnt/β-catenin pathway
Angiogenesis ( IF 9.2 ) Pub Date : 2021-03-02 , DOI: 10.1007/s10456-021-09773-x
Bing Liu _{1,

2} , Han Zhou _{1,

2} , Tiening Zhang _{1,

2,

3} , Xixiang Gao _{2,

4} , Bo Tao _{2,

5} , Hao Xing _{2,

6} , Zhenwu Zhuang _{7,

8} , Alan Dardik _{2,

9,

10} , Themis R Kyriakides _{2,

6,

11} , Julie E Goodwin _{1,

2}

Affiliation

Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06520, USA.
Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA.
Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, 110004, China.
Department of Vascular Surgery, Xuanwu Hospital, Capital Medical University and Institute of Vascular Surgery, Capital Medical University, Beijing, China.
Department of Pharmacology, Yale University School of Medicine, New Haven, CT, 06520, USA.
Department of Biomedical Engineering, Yale University School of Medicine, New Haven, CT, 06510, USA.
Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.
Department of Internal Medicine, Yale Cardiovascular Research Center, New Haven, CT, 06510-3221, USA.
Department of Surgery, Yale University School of Medicine, New Haven, CT, 06520, USA.
Department of Surgery, VA Connecticut Healthcare Systems, West Haven, CT, 06516, USA.
Department of Pathology, Yale University, New Haven, CT, 06510, USA.

Objective

The glucocorticoid receptor (GR) is a member of the nuclear receptor family that controls key biological processes in the cardiovascular system and has recently been shown to modulate Wnt signaling in endothelial cells. Wnt/β-catenin signaling has been demonstrated to be crucial in the process of angiogenesis. In the current study, we studied whether GR could regulate angiogenesis via the Wnt/β-catenin pathway.

Approach and Resultsa

Key components of the Wnt/β-catenin pathway were evaluated using quantitative PCR and Western blot in the presence or absence of GR. Enhanced angiogenesis was found in GR deficiency in vitro and confirmed with cell viability assays, proliferation assays and tube formation assays. Consistent with these in vitro findings, endothelial cell-specific GR loss GR in vivo promoted angiogenesis in both a hind limb ischemia model and sponge implantation assay. Results were further verified in a novel mouse model lacking endothelial LRP5/6, a key receptor in canonical Wnt signaling, and showed substantially suppressed angiogenesis using these same in vitro and in vivo assays. To further investigate the mechanism of GR regulation of Wnt signaling, autophagy flux was investigated in endothelial cells by visualizing auto phagolysosomes as well as by assessing P62 degradation and LC3B conversion. Results indicated that potentiated autophagy flux participated in GR-Wnt regulation.

Conclusions

Lack of endothelial GR triggers autophagy flux, leads to activation of Wnt/β-catenin signaling and promotes angiogenesis. There may also be a synergistic interaction between autophagy and Wnt/β-catenin signaling.

中文翻译：

内皮糖皮质激素受体缺失通过上调 Wnt/β-catenin 通路促进血管生成

客观的

糖皮质激素受体 (GR) 是控制心血管系统关键生物过程的核受体家族的成员，最近已显示可调节内皮细胞中的 Wnt 信号传导。Wnt/β-连环蛋白信号已被证明在血管生成过程中至关重要。在目前的研究中，我们研究了 GR 是否可以通过 Wnt/β-catenin 途径调节血管生成。

方法和结果a

在存在或不存在 GR 的情况下，使用定量 PCR 和蛋白质印迹评估 Wnt/β-连环蛋白途径的关键成分。在体外 GR 缺陷中发现了增强的血管生成，并通过细胞活力测定、增殖测定和管形成测定得到证实。与这些体外研究结果一致，体内内皮细胞特异性 GR 损失 GR 在后肢缺血模型和海绵植入试验中促进了血管生成。结果在缺乏内皮 LRP5/6（经典 Wnt 信号传导中的关键受体）的新型小鼠模型中得到进一步验证，并显示使用这些相同的体外和体内测定显着抑制血管生成。为了进一步研究GR调控Wnt信号的机制，通过观察自噬溶酶体以及评估 P62 降解和 LC3B 转化，在内皮细胞中研究自噬通量。结果表明，增强的自噬通量参与了 GR-Wnt 的调节。