Roxadustat promotes angiogenesis through HIF‐1α/VEGF/VEGFR2 signaling and accelerates cutaneous wound healing in diabetic rats

Abstract

Diabetic foot ulcers are a major health‐care burden worldwide. One primary cause of the delayed wound healing in diabetic patients is impaired function of the hypoxia‐inducible factor‐1α/vascular endothelial growth factor (HIF‐1α/VEGF) axis, which results in compromised neovascularization in response to hypoxia. In the present study, we aimed to investigate the effect of roxadustat, a novel HIF prolyl‐4‐hydroxylase inhibitor, on angiogenesis and its therapeutic effect on cutaneous wound healing in diabetic rats. In vitro, we found that roxadustat could promote the angiogenic activity of human umbilical vein endothelial cells, accompanied by up‐regulation of HIF‐1α/VEGF/VEGFR2 signaling. Next, we demonstrated that Ki8751, a VEGFR2‐specific inhibitor, could inhibit the increased angiogenic activity of human umbilical vein endothelial cells induced by roxadustat. In vivo, we performed a Matrigel plug assay and demonstrated that roxadustat induced vascularization of the Matrigel plugs, and this effect could be partially inhibited by Ki8751. Finally, we utilized a streptozotocin‐induced diabetic rat model and found that roxadustat could accelerate cutaneous wound healing and promote angiogenesis in the wound sites. In conclusion, roxadustat promotes angiogenesis via activation of the HIF‐1α/VEGF/VEGFR2 pathway and exhibits therapeutic effects on diabetic wound healing by increasing angiogenesis. Our findings suggest that roxadustat can be a promising strategy to promote diabetic cutaneous wound healing.

Hypoxia and hypoxia-inducible factors in diabetes and its complications

“…Moreover, elevated fatty acids can promote PHD-mediated HIF-1α degradation by decreasing succinate levels in type 2 diabetes. This figure is available as part of a downloadable slideset signalling contributes to impaired wound healing in diabetes, with induction of HIF-1 function promoting wound healing by increasing angiogenesis and fibroblast proliferation and migration in mouse models of diabetes [11,20,21]. As an iron-chelating agent clinically used to treat iron toxicity, deferoxamine (desferrioxamine) can reduce oxidative stress and induce HIF-1 activation, thereby accelerating diabetic wound healing [20].…”

“…Pharmacological induction of HIF-1 promotes wound healing in experimental diabetes models [11,20,21]. Recent preclinical studies in diabetic animal models have shown that PHD inhibition can also prevent the progression of diabetic nephropathy [8,27] and atherosclerosis [29], protect the ischaemic heart [14,51] and peripheral neuron [52], and improve cognitive function [53].…”

Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice

“…12 Roxadustat (FG-4592) is a novel, potent HIF PHD inhibitor that can stabilize HIF-1a under normoxic or hyperoxic conditions. 17 It stimulates endogenous erythropoietin production and is currently being tested for the treatment of anemia in chronic kidney disease. 18 Roxadustat rescued hepatic Hif1a-gene-knockout neonatal mice from retinal oxygen toxicity, overriding the ablation of hepatic HIF-1a by directly targeting retinal tissue.…”

Ultrastructural studies of the neurovascular unit reveal enhanced endothelial transcytosis in hyperglycemia‐enhanced hemorrhagic transformation after stroke

“…We also confirmed that the increased vesicles may result from both caveolin‐ and clathrin‐mediated endocytosis pathways. Diabetes elevates the expression of HIF‐1α and vascular endothelial growth factor (VEGF) in the ischemic cerebral microvasculature, 38,50,51 which is accompanied by the disruption of the BBB, increased infarct volume, severe edema formation, and exacerbated neurological deficits. Specific inhibition of endothelial HIF‐1α could partially reverse the damaging effects of diabetes on cerebrovascular injury, suggesting that HIF‐1α activation is one important mechanism underlying increased BBB permeability 38 .…”