Abstract
Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide due to increasing survival rates of premature infants. Initial suppression, followed by increased production of the retinal vascular endothelial growth factor-A (VEGF) expression are key events that trigger the pathological neovascularization in ROP. Fatty acid binding protein 4 (FABP4) is an intracellular lipid chaperone that is induced by VEGF in a subset of endothelial cells. FABP4 exhibits a pro-angiogenic function in cultured endothelial cells and in airway microvasculature, but whether it plays a role in modulation of retinal angiogenesis is not known. We hypothesized that FABP4 deficiency could ameliorate pathological retinal vascularization and investigated this hypothesis using a well-characterized mouse model of oxygen-induced retinopathy (OIR). We found that FABP4 was not expressed in retinal vessels, but was present in resident macrophages/microglial cells and endothelial cells of the hyaloid vasculature in the immature retina. While FABP4 expression was not required for normal development of retinal vessels, FABP4 expression was upregulated and localized to neovascular tufts in OIR. FABP4−/− mice demonstrated a significant decrease in neovessel formation as well as a significant improvement in physiological revascularization of the avascular retinal tissues. These alterations in retinal vasculature were accompanied by reduced endothelial cell proliferation, but no effect on apoptosis or macrophage/microglia recruitment. FABP4−/− OIR samples demonstrated decreased expression of genes involved in angiogenesis, such as Placental Growth Factor, and angiopoietin 2. Collectively, our findings suggest FABP4 as a potential target of pathologic retinal angiogenesis in proliferative retinopathies.
Highlights
Retinopathy of prematurity (ROP) has become a leading cause of blindness in children worldwide due to increasing survival rates of premature infants[1]
These results demonstrate that Fatty acid binding protein 4 (FABP4) expression is not required for normal development of retinal vessels
In this study we found that genetic deficiency of FABP4 provides significant protection against the development of oxygen-induced retinopathy (OIR) in
Summary
Retinopathy of prematurity (ROP) has become a leading cause of blindness in children worldwide due to increasing survival rates of premature infants[1]. In contrast to pan-endothelial cell markers, such as CD31, FABP4 expression is restricted to microvascular and small vascular ECs, which are actively involved in angiogenic responses Consistent with this notion, deficiency of EC-FABP4 leads to attenuation of angiogenic responses, such as cell proliferation, migration, survival, and morphogenesis through modulation of several pathways, including eNOS and SCF/c-kit signaling[19,22]. Studies in human subjects with glioblastoma, the most malignant primary brain tumor in adults associated with robust angiogenic activity, revealed FABP4 expression in a subset of ECs, which was not detected in control specimens[21] Taken together, these studies have suggested that FABP4 might enhance pathological angiogenesis, which plays a role in the pathogenesis of ROP. We hypothesized that genetic deficiency of FABP4 could ameliorate pathological retinal neovascularization that occurs in ROP and investigated this hypothesis using a well-characterized mouse model of oxygeninduced retinopathy (OIR)[24]
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