Abscisic acid – an anti-angiogenic phytohormone that modulates the phenotypical plasticity of endothelial cells and macrophages

Abstract

Abscisic acid (ABA) has shown anti-inflammatory and immunoregulatory properties in preclinical models of diabetes and inflammation. Herein, we studied the effects of ABA on angiogenesis, a strictly controlled process that, when dysregulated, leads to severe angiogenic disorders including vascular overgrowth, exudation, cellular inflammation and organ dysfunction. By 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 and 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 M1 phenotype characterized by anti-angiogenic marker expression. In accordance with this, 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 as a treatment in vasoproliferative diseases.

CCN1–Yes-Associated Protein Feedback Loop Regulates Physiological and Pathological Angiogenesis

“…Since our studies showed that the interplay among CCN1 signaling, cytoskeletal architecture, and YAP transcriptional activation normalizes angiogenesis in the retina, we postulated that they could serve as potential molecular tools to correct vascular abnormalities. Therefore, we investigated the functional relevance of CCN1-YAP cross talk in pathological angiogenesis using mice with oxygen-induced retinopathy (OIR), a model of ischemia-induced VEGF-dependent retinal neovascularization (32,33). Mice were subjected to hyperoxia from P7 to P12 to induce vaso-obliteration and normoxia until P17 to produce maximal preretinal neovascularization ( Fig.…”

Macrophage functions in wound healing

“…This study indicates that retinoic acid improves healing process through its stimulatory effect on macrophages. Chaqour, Lee, Ravichandra, and Chaqour () studied the effect of abscisic acid (ABA)—a plant hormone (involved in plant stress response and plant buds dormancy) on the retinal and fetal angiogenesis, using a 3D sprouting assay methodology in retinal vasculature mice model. They showed that ABA inhibits development and regeneration of blood vessels and speeds up macrophage‐induced programmed regression of fetal blood vessels.…”

Is There A Role for Abscisic Acid, A Proven Anti-Inflammatory Agent, in the Treatment of Ischemic Retinopathies?

“…Anti-VEGF strategies, which include neutralization by engineered antibodies, chimeric receptors, or laser treatment that alleviates ischemia, an important stimulus for VEGF expression, have been proposed as promising therapies [15,27]. Although partially effective, several side adverse effects have been associated with anti-VEGF agents, including visual impairment since this growth factor has also been shown to have neuroprotective functions in the survival of retinal ganglion cells [28].…”

“…At the moment, there is almost no literature about the direct functional effects of ABA in this neurosensorial tissue. However recently, Chaqour and coworkers have studied the effects of ABA administration on physiological and pathological angiogenesis processes in the retina, particularly in a mouse model of OIR [27]. Interestingly, they showed that this phytohormone acts largely by altering the phenotypical plasticity of endothelial cells and skewing the canonical polarized inflammatory statuses of macrophages towards an antiangiogenic phenotype.…”

“…Although ABA did not affect macrophage infiltration of the ischemic areas in the retina, the treatment with this phytohormone significantly increased the amount of OIR-induced anti-angiogenic macrophage markers and dampened pro-angiogenic macrophage-related markers. It is especially noteworthy that ABA also reduced significantly VEGF expression in the retina, which is the major growth factor involved in angiogenesis [27].…”