1α,25-Dihydroxyvitamin D3 promotes angiogenesis by alleviating AGEs-induced autophagy
2021
Xiong, Yi | Zhou, Feng | Liu, Yeyu | Yi, Zumu | Wang, Xinyu | Wu, Yingying | Gong, Ping
Diabetes mellitus (DM) induces abnormal angiogenesis and results in multiple chronic vascular complications. Previous studies showed that advanced glycation end products (AGEs) up-regulated in diabetic patients and induced a series of cellular effects such as oxidative stress, inflammation, and autophagy. 1α,25-Dihydroxyvitamin D3 (1,25D), a hormonal form of vitamin D, proved to be beneficial for vascular diseases. However, the underlying mechanism of 1,25D in angiogenesis in DM remains unclear. Using CCK8 assay and transwell assay, we found that 1,25D could partly ameliorate impaired proliferation and migration ability of endothelial cells (ECs) induced by AGEs (200 μg/mL). Furthermore, tube formation assay, Western blot, and real-time qPCR assay were conducted to demonstrate that AGEs impaired angiogenetic ability, and that angiogenesis-related gene expression (i.e., VEGFA, VEGFB, VEGFR1, VEGFR2, TGFβ1, MMP2, MMP9) in ECs and 1,25D could promote angiogenesis and angiogenetic markers expression. By using DCFH-DA, ELISA, and Western blot assay, we also found that AGEs-induced oxidative stress impaired angiogenic ability of ECs, and 1,25D alleviated angiogenesis dysfunction by inhibiting oxidative stress. Of note, AGEs-induced excessive autophagy was found to impair angiogenesis. We elucidated that the detrimental autophagy is modulated by 1,25D and AGEs via PI3K/Akt pathway. Observed together, our findings illustrated that AGEs-induced oxidative stress and autophagy resulted in angiogenic disorder and 1,25D improved angiogenesis by restraining excessive autophagy and oxidative stress, providing a novel insight for the treatment of vascular complications in DM.
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