Erianin inhibits high glucose-induced retinal angiogenesis via blocking ERK1/2-regulated HIF-1α-VEGF/VEGFR2 signaling pathway

Abstract

Erianin is a natural compound found in Dendrobium chrysotoxum Lindl. Diabetic retinopathy (DR) is a serious and common microvascular complication of diabetes. This study aims to investigate the inhibitory mechanism of erianin on retinal neoangiogenesis and its contribution to the amelioration of DR. Erianin blocked high glucose (HG)-induced tube formation and migration in choroid-retinal endothelial RF/6A cells. Erianin inhibited HG-induced vascular endothelial growth factor (VEGF) expression, hypoxia-inducible factor 1-alpha (HIF-1α) translocation into nucleus and ERK1/2 activation in RF/6A and microglia BV-2 cells. MEK1/2 inhibitor U0126 blocked HG-induced HIF-1α and ERK1/2 activation in both above two cells. In addition, erianin abrogated VEGF-induced angiogenesis in vitro and in vivo, and also inhibited VEGF-induced activation of VEGF receptor 2 (VEGFR2) and its downstream cRaf-MEK1/2-ERK1/2 and PI3K-AKT signaling pathways in RF/6A cells. Furthermore, erianin reduced the increased retinal vessels, VEGF expression and microglia activation in streptozotocin (STZ)-induced hyperglycemic and oxygen-induced retinopathy (OIR) mice. In conclusion, our results demonstrate that erianin inhibits retinal neoangiogenesis by abrogating HG-induced VEGF expression by blocking ERK1/2-mediated HIF-1α activation in retinal endothelial and microglial cells, and further suppressing VEGF-induced activation of VEGFR2 and its downstream signals in retinal endothelial cells.

Long non-coding RNA DANCR alleviates hypoxia-caused H9c2 cells damage through up regulation of HIF-1α

“…For example, hypoxiacaused the up-regulation of HIF-1a could be inhibited by the inactivation of PI3K/AKT/mTOR pathway in human glioblastoma cells [29]. Besides, erianin-caused the inhibition of ERK1/ 2 pathway resulted in its blockage on HIF-1a in high glucosecaused retinal angiogenesis [30]. These findings revealed the positive regulation mechanism of these pathways on HIF-1a.…”

Nogo‐A inhibits vascular regeneration in ischemic retinopathy

“…The level of phospho-VEGFR2 did not significantly vary between αBrdU and 11C7 treatments (Supporting Information Figure S6b) in P13 OIR retina. The activation of signaling cascades involved in pathological angiogenesis such as P-Stat3 (Sun et al, 2015), P-S6 (Yagasaki et al, 2014), and P-Erk1/2 (Yu et al, 2016) were also not influenced by 11C7 injection (Supporting Information Figure 6a,b). These results suggest that 11C7 may promote in part vascular growth by decreasing S1PR2 in endothelial cells.…”

A Critical Analysis of the AvailableIn VitroandEx VivoMethods to Study Retinal Angiogenesis

“…To study angiogenesis, specifically in the retina, it is better to use ECs from retinal tissue, since there are unique properties of ECs obtained from different organs. The most used retinal ECs are bovine retinal endothelial cells (BRECs) [ 13 – 37 ], human retinal endothelial cells (HRECs) [ 18 , 24 , 38 – 77 ], and Rhesus monkey retinal and choroid endothelial cells (RF/6a) [ 78 – 94 ] ( Figure 2 ). Only one study used Rhesus monkey retinal endothelial cells [ 95 ].…”

“…The reported incubation period varies between 4 hours and 72 hours. The minimal incubation period in standard matrigel was 4 hours [ 94 , 124 ], while in GF-reduced matrigel was 6 hours [ 72 , 77 ]. Some studies used different matrices from several angiogenesis assays since nowadays there are several laboratories purchasing angiogenesis kits, all based on the matrix method.…”