PUBLICATION

Vitamin D Receptor Agonists Regulate Ocular Developmental Angiogenesis and Modulate Expression of dre-miR-21 and VEGF

Authors
Merrigan, S.L., Kennedy, B.N.
ID
ZDB-PUB-170527-2
Date
2017
Source
British journal of pharmacology   174(16): 2636-2651 (Journal)
Registered Authors
Kennedy, Breandan N.
Keywords
none
MeSH Terms
  • Angiogenesis Inhibitors/pharmacology*
  • Animals
  • Animals, Genetically Modified
  • Calcitriol/pharmacology
  • Eye/blood supply
  • Eye/drug effects*
  • Eye/growth & development
  • Eye/metabolism
  • Larva
  • MicroRNAs/metabolism
  • Neovascularization, Physiologic/drug effects*
  • Receptors, Calcitriol/agonists*
  • Tretinoin/pharmacology
  • Vascular Endothelial Growth Factor A/metabolism
  • Zebrafish
  • Zebrafish Proteins/metabolism
PubMed
28547797 Full text @ Br. J. Pharmacol.
Abstract
Pathological growth of ocular vasculature networks can underpin visual impairment in neovascular age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity. Our aim was to uncover novel pharmacological regulators of ocular angiogenesis by phenotype-based screening in zebrafish.
A bioactive chemical library of 465 drugs was screened to identify small molecule inhibitors of ocular hyaloid vasculature (HV) angiogenesis in zebrafish larvae. Selectivity was assessed by evaluation of non-ocular intersegmental vasculature development. Safety pharmacology examined visual behaviour and retinal histology in larvae. Molecular mechanisms of action were interrogated using expression profiling of target mRNAs and miRNAs in larval eyes.
Library screening identified 10 compounds which significantly inhibited HV developmental angiogenesis. Validated hit calcitriol selectively demonstrated dose-dependent attenuation of HV development. In agreement, vitamin D receptor (VDR) agonists paricalcitol, doxercalciferol, maxacalcitol, calcipotriol, seocalcitol, calcifediol and tacalcitol significantly and selectively attenuated HV development. VDR agonists induced minor ocular morphology abnormalities and affected normal visual function. Calcitriol induced a 3-7-fold increase in ocular dre-miR-21 expression. Consistently, all-trans-retinoic acid attenuated HV development and increased ocular dre-miR-21 expression. Interestingly, zebrafish ocular vegfaa and vegfab expression was significantly increased while, vegfc, flt1 and kdrl expression was unchanged by calcitriol.
These studies identify VDR agonists as significant and selective anti-angiogenics in the developing vertebrate eye and miR21 as a key downstream regulated miRNA. These targets should be further evaluated as molecular hallmarks of, and therapeutic targets for pathological ocular neovascularisation.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping