Attenuation of EphrinB2 Reverse Signaling Decreases Vascularized Area and Preretinal Vascular Tuft Formation in the Murine Model of Oxygen-Induced Retinopathy

Abstract

EphrinB2 reverse signaling is a regulator of key processes during retinal vascularization and controls pathologic retinal angiogenesis through direct effects on capillary sprouting and endothelial filopodia formation.

Retinal Angiogenesis in the Ins2AkitaMouse Model of Diabetic Retinopathy

“…40,41 In spite of the myriad signs of vascular disease we see in the Ins2 Akita mice, it is important to recognize that we do not detect signs of preretinal neovascularization (a common phenotype of proliferative DR), in these mice, and studies targeting this particular phenotype may need to consider other models such as the opticin knockout mouse 42 or the oxygeninduced retinopathy model. 43,44 The retinal microangiopathy caused by diabetes is a complex disease that is strictly controlled by a spectrum of pro-and anti-inflammatory factors, pro-and antiangiogenic factors, as well as other factors such as proteases, extracellular matrix proteins, chemokines, vasoactive hormones, immune cells, and adhesion molecules. [45][46][47] Changes in other pathways such as the oxidative stress pathway, 48 the nonspecific inflammation pathway, 49 and the endoplasmic reticulum stress pathway 50 have also been reported in DR.…”

Regulation of signaling interactions and receptor endocytosis in growing blood vessels

“…64,65,109 Ephrin-B2 and EphB4 show partially overlapping expression in the angiogenic growth front and are presumably also active in the neovascular sprouts and blindended capillaries during hypoxia-induced angiogenesis in oxygen-induced retinopathy, a model for pathological vessel growth in the eye. 64,110 Ephrin-B2 overexpression stimulated endothelial motility and invasiveness in cultured cells and transgenic mice. 64,65,111 Conversely, ephrin-B2 conditional deletion in endothelium or deletion of the C-terminal PDZ binding motif (in ephrin-B2DV mutants) impaired sprouting angiogenesis in physiological and pathological conditions.…”

“…64,65 When the ephrin-B2 cytoplasmic domain was replaced by b-galactosidase, retina vascularization and filopodia formation were reduced. 110 Likewise, revascularization and the formation of vascular malformations, so-called neovascular tufts, were attenuated when these mutants were analyzed under conditions of oxygen-induced retinopathy. 110 The 2 main signaling pathways known to reciprocally regulate and cooperate in the specification of tip-stalk cell phenotypes during angiogenesis are VEGF and Notch.…”

“…110 Likewise, revascularization and the formation of vascular malformations, so-called neovascular tufts, were attenuated when these mutants were analyzed under conditions of oxygen-induced retinopathy. 110 The 2 main signaling pathways known to reciprocally regulate and cooperate in the specification of tip-stalk cell phenotypes during angiogenesis are VEGF and Notch. 32 VEGF promotes Dll4 ligand expression in tip cells.…”

Expression of ephrinB2 and EphB4 in a neonatal rat model of periventricular white matter damage

“…However, no effect of experimental hypoxia on either ephrinB2 and EphB4 gene expression or protein synthesis was observed in human melanoma cells in vitro [23]. In oxygen-induced retinopathy of prematurity, expression of ephrinB2 and EphB4 receptors was detected in harvested retinal fibroproliferative membranes [5,24]. In the adult mammalian CNS, EphB4 and ephrinB2 are expressed in the subventricular zone of the lateral ventricle and in the rostral migratory stream, which constitutes an ongoing neurogenic pathway, and in various cell types including neurons, oligodendrocytes and reactive astrocytes that are in contact with blood vessels or closely associated with the pial surface.…”