Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Yishan Rd 600, Shanghai 200233, PR China.
Wound Repair Regen. 2019 Jul;27(4):324-334. doi: 10.1111/wrr.12708. Epub 2019 Feb 28.
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.
糖尿病足溃疡是全球范围内的一个主要医疗保健负担。糖尿病患者伤口愈合延迟的一个主要原因是缺氧诱导因子-1α/血管内皮生长因子（HIF-1α/VEGF）轴功能受损，导致缺氧时新血管生成受损。在本研究中，我们旨在研究新型 HIF 脯氨酰-4-羟化酶抑制剂罗沙司他对血管生成的影响及其对糖尿病大鼠皮肤伤口愈合的治疗作用。在体外，我们发现罗沙司他可以促进人脐静脉内皮细胞的血管生成活性，同时上调 HIF-1α/VEGF/VEGFR2 信号通路。接下来，我们证明了 VEGFR2 特异性抑制剂 Ki8751 可以抑制罗沙司他诱导的人脐静脉内皮细胞血管生成活性的增加。在体内，我们进行了 Matrigel plugs 实验，证明罗沙司他诱导了 Matrigel plugs 的血管化，而 Ki8751 可以部分抑制这种作用。最后，我们利用链脲佐菌素诱导的糖尿病大鼠模型发现，罗沙司他可以加速皮肤伤口愈合并促进伤口部位的血管生成。总之，罗沙司他通过激活 HIF-1α/VEGF/VEGFR2 通路促进血管生成，并通过增加血管生成对糖尿病伤口愈合发挥治疗作用。我们的研究结果表明，罗沙司他可以成为促进糖尿病皮肤伤口愈合的一种有前途的策略。
