Abstract
The maintenance of fluid homeostasis is necessary for function of the neural retina; however, little is known about the significance of potential fluid management mechanisms. Here, we investigated angiopoietin-4 (Angpt4, also known as Ang3), a poorly characterized ligand for endothelial receptor tyrosine kinase Tie2, in mouse retina model. By using genetic reporter, fate mapping, and in situ hybridization, we found Angpt4 expression in a specific sub-population of astrocytes at the site where venous morphogenesis occurs and that lower oxygen tension, which distinguishes peripheral and venous locations, enhances Angpt4 expression. Correlating with its spatiotemporal expression, deletion of Angpt4 resulted in defective venous development causing impaired venous drainage and defects in neuronal cells. In vitro characterization of angiopoietin-4 proteins revealed both ligand-specific and redundant functions among the angiopoietins. Our study identifies Angpt4 as the first growth factor for venous-specific development and its importance in venous remodeling, retinal fluid clearance and neuronal function.
Highlights
Maintenance of fluid homeostasis is necessary for normal functions of the retina
The same expression pattern was detected in Angpt4Cre; Rosa26mT/mG mouse retina (Figure 1C–G), but not in controls (Figure 1—figure supplement 2A–E)
Using inhibitors against plasmin/serine proteases, PI3K (BYL719 and LY294002) and shRNA constructs directed against TIE2 (Figure 8A–D), we found that to ANGPT1, Angpt4 and ANGPT4 induced growth of luminal structures TIE2, PI3K and serine protease dependently
Summary
Maintenance of fluid homeostasis is necessary for normal functions of the retina. Defects in supporting mechanisms result in macular edema that is the major cause of vision loss in common vascular and inflammatory diseases including diabetes, retinal vein occlusions and neovascularization affecting millions of people globally (Daruich et al, 2018). Excess of exogenous Angpt or ANGPT4 induced blood and lymphatic vascular remodeling (Kim et al, 2007; Lee et al, 2004) and ANGPT4 improved vascular function in Elamaa et al eLife 2018;7:e37776. To clarify the physiological importance of Angpt, we generated independently targeted mouse alleles to investigate cellular source, regulation of expression and the effect of Angpt deficiency in mouse retina that provides a widely used model for blood vessel growth, remodeling, maturation and vascular pathologies. Angpt deficiency did not affect capillaries or arteries either in physiological development, during aging or in retinopathy in OIR model, indicating a venous-specific function. Our data reveals functional importance of a specific vein type in the peripheral retina, novel aspects of the complex Angpt/Tie pathway and complementary roles for angiopoietins in the establishment of the retinal circulatory system
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