Activation of Retinal Angiogenesis in Hyperglycemic <i>pdx1</i> ^<i>-/-</i> Zebrafish Mutants.

Abstract

Progression from the initial vascular response upon hyperglycemia to a proliferative stage with neovacularizations is the hallmark of proliferative diabetic retinopathy. Here, we report on the novel diabetic <i>pdx1</i> ^<i>-/-</i> zebrafish mutant as a model for diabetic retinopathy that lacks the transcription factor <i>pdx1</i> through CRISPR-Cas9-mediated gene knockout leading to disturbed pancreatic development and hyperglycemia. Larval <i>pdx1</i> ^<i>-/-</i> mutants prominently show vasodilation of blood vessels through increased vascular thickness in the hyaloid network as direct developmental precursor of the adult retinal vasculature in zebrafish. In adult <i>pdx1</i> ^<i>-/-</i> mutants, impaired glucose homeostasis induces increased hyperbranching and hypersprouting with new vessel formation in the retina and aggravation of the vascular alterations from the larval to the adult stage. Both vascular aspects respond to antiangiogenic and antihyperglycemic pharmacological interventions in the larval stage and are accompanied by alterations in the nitric oxide metabolism. Thus, the <i>pdx1</i> ^<i>-/-</i> mutant represents a novel model to study mechanisms of hyperglycemia-induced retinopathy wherein extensive proangiogenic alterations in blood vessel morphology and metabolic alterations underlie the vascular phenotype.