Abstract
ObjectiveThe 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 ResultsaKey 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.ConclusionsLack 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.
Highlights
Angiogenesis, defined as the formation of new capillaries from pre-existing blood vessels, is an essential physiological process involved in wound healing, ovulation, vascular and embryonic development [1]
Given the interest in better determining the links between autophagy, angiogenesis and cancer [24], we aimed to investigate whether glucocorticoid receptor (GR) could regulate angiogenesis via the Wnt signaling pathway and whether GR could regulate Wnt signaling through autophagy flux
MLECs were stained with antibodies against β-catenin and GR and showed that GR deficiency contributed to the accumulation of β-catenin in the nucleus (Suppl Fig. S1a and S1b)
Summary
Angiogenesis, defined as the formation of new capillaries from pre-existing blood vessels, is an essential physiological process involved in wound healing, ovulation, vascular and embryonic development [1]. It is a complex process characterized by the migration of endothelial tip and stalk cells in response to a variety of stimuli including chemokines and growth factors such as VEGFA, and is regulated by a variety of signaling pathways [2]. The development of angiogenesis inhibitors and immunotherapies represents an active area of investigation to combat cancer and other sequelae of dysregulated angiogenesis [4,5,6]. Further investigation of underlying molecular mechanisms of angiogenesis is critical to understanding these common disease processes
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