Merrigan Stephanie L, Park Bomina, Ali Zaheer, Jensen Lasse D, Corson Timothy W, Kennedy Breandán N
UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin D04 V1W8, Ireland.
Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Oncotarget. 2020 Feb 4;11(5):493-509. doi: 10.18632/oncotarget.27380.
Aberrant ocular angiogenesis can underpin vision loss in leading causes of blindness, including neovascular age-related macular degeneration and proliferative diabetic retinopathy. Current pharmacological interventions require repeated invasive administrations, may lack efficacy and are associated with poor patient compliance and tachyphylaxis. Vitamin D has anti-angiogenic properties. Here, our aim was to validate the ocular anti-angiogenic activity of biologically active vitamin D, calcitriol, and selected vitamin D analogue, 22-oxacalcitriol. Calcitriol induced a significant reduction in mouse choroidal fragment sprouting. Viability studies in a human RPE cell line suggested non-calcemic vitamin D analogues including 22-oxacalcitriol have less off-target anti-proliferative activity compared to calcitriol and other analogues. Thereafter, the anti-angiogenic activity of 22-oxacalcitriol was demonstrated in an mouse choroidal fragment sprouting assay. In zebrafish larvae, 22-oxacalcitriol was found to be anti-angiogenic, inducing a dose-dependent reduction in choriocapillaris development. Subcutaneously administered calcitriol failed to attenuate mouse retinal vasculature development. However, calcitriol and 22-oxacalcitriol administered intraperitoneally, significantly attenuated lesion volume in the laser-induced choroidal neovascularisation mouse model. In summary, calcitriol and 22-oxacalcitriol attenuate and choroidal vasculature angiogenesis. Therefore, vitamin D may have potential as an interventional treatment for ophthalmic neovascular indications.
异常的眼部血管生成可能是导致失明的主要原因（包括新生血管性年龄相关性黄斑变性和增殖性糖尿病视网膜病变）中视力丧失的基础。目前的药物干预需要反复进行侵入性给药，可能缺乏疗效，并且与患者依从性差和快速耐受有关。维生素D具有抗血管生成特性。在这里，我们的目的是验证生物活性维生素D、骨化三醇和选定的维生素D类似物22-氧杂骨化三醇的眼部抗血管生成活性。骨化三醇可显著减少小鼠脉络膜碎片的发芽。在人视网膜色素上皮细胞系中的活力研究表明，与骨化三醇和其他类似物相比，包括22-氧杂骨化三醇在内的非钙血症维生素D类似物具有较少的脱靶抗增殖活性。此后，在小鼠脉络膜碎片发芽试验中证明了22-氧杂骨化三醇的抗血管生成活性。在斑马鱼幼虫中，发现22-氧杂骨化三醇具有抗血管生成作用，可导致脉络膜毛细血管发育呈剂量依赖性减少。皮下注射骨化三醇未能减弱小鼠视网膜血管系统的发育。然而，腹腔注射骨化三醇和22-氧杂骨化三醇可显著减小激光诱导的脉络膜新生血管小鼠模型中的病变体积。总之，骨化三醇和22-氧杂骨化三醇可减弱脉络膜血管生成。因此，维生素D可能具有作为眼科新生血管适应症干预治疗的潜力。
