Abscisic acid: an antiangiogenic phytohormone that modulates the phenotypical plasticity of endothelial cells and macrophages

Abstract

Abscisic acid (ABA) has shown antiinflammatory and immunoregulatory properties in preclinical models of diabetes and inflammation. Herein, we studied the effects of ABA on angiogenesis, a strictly controlled process which when dysregulated, leads to severe angiogenic disorders including vascular overgrowth, exudation, cellular inflammation and organ dysfunction. Using a 3D sprouting assay, we show that ABA effectively inhibits migration, growth, and expansion of endothelial tubes without affecting cell viability. Analyses of the retinal vasculature in developing normoxic and hyperoxic mice challenged by oxygen toxicity reveal that exogenously administered ABA stunts the development and regeneration of blood vessels. In these models, ABA downregulates endothelial cell (EC)-specific growth and migratory genes, interferes with tip/stalk cell specification, and hinders the function of filopodial protrusions required for precise guidance of vascular sprouts. In addition, ABA skews macrophage polarization towards the destructive M1 phenotype characterized by antiangiogenic marker expression. Concordantly, ABA treatment accelerates macrophage-induced programmed regression of fetal blood vessels. These findings reveal protective functions of ABA against neovascular growth through modulation of EC and macrophage plasticity, suggesting the potential utility of ABA in vasoproliferative diseases.