Calcitriol and non-calcemic vitamin D analogue, 22-oxacalcitriol, attenuate developmental and pathological choroidal vasculature angiogenesis ex vivo and in vivo

// Stephanie L. Merrigan 1 , Bomina Park 2 , 3 , Zaheer Ali 4 , Lasse D. Jensen 4 , Timothy W. Corson 2 , 3 and Breandan N. Kennedy 1 1 UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin D04 V1W8, Ireland 2 Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, USA 3 Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis,Indiana, USA 4 Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linkoping University, Linkoping, Sweden Correspondence to: Breandan N. Kennedy, email: brendan.kennedy@ucd.ie Keywords: developmental angiogenesis; pathological angiogenesis; ocular angiogenesis; calcitriol; 22-oxacalcitriol Received: July 22, 2019     Accepted: October 19, 2019     Published: February 04, 2020 ABSTRACT 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 de novo 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 ex vivo 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 ex vivo 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 ex vivo and in vivo choroidal vasculature angiogenesis. Therefore, vitamin D may have potential as an interventional treatment for ophthalmic neovascular indications.