Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.
Invest Ophthalmol Vis Sci. 2012 Aug 13;53(9):5462-70. doi: 10.1167/iovs.11-8599.
EphB4 and ephrinB2 are known key regulators of retinal vascular development, but due to their capacity for bidirectional signaling, delineation of their individual roles in this process remains unclear. To better dissect out individual contributions, a model of proliferative retinopathy in mice with attenuated ephrinB2 reverse signaling was studied. It was hypothesized that endothelial ephrinB2 reverse signaling regulates hypoxia-induced capillary sprouting, as well as the pathologic formation of neovascular tufts in postnatal retinal microvascular networks.
Genetically manipulated mice with attenuated ephrinB2 reverse signaling (ephrinB2(lacZ/+)), along with wild-type (WT) controls, were exposed to oxygen-induced retinopathy (OIR), a postnatal model of proliferative retinopathy. At peak disease (postnatal day 18), microvascular networks were analyzed to examine intraretinal revascularization, capillary sprouting, and pathologic neovascularization responses. EphB4 and phosphorylated ephrinB protein expression patterns along retinal microvessels were also assessed.
EphrinB2(lacZ/+) mice exhibited reduced hypoxia-induced revascularization (P ≤ 0.04) and reduced formation of neovascular tufts (P < 0.001), as compared with WT controls. Corresponding to the observed inhibition of retinal angiogenesis, ephrinB2(lacZ/+) retinas displayed an increased number of blind-ended capillary sprout tips (P < 0.02) and endothelial filopodial processes (P = 0.001). In WT and ephrinB2(lacZ/+) OIR-exposed retinas, ephrinB was confined to endothelial cells, with expression detected along angiogenic vascular processes including neovascular tufts and blind-ended capillary sprouts.
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.
EphB4 和 ephrinB2 是已知的视网膜血管发育的关键调节因子，但由于它们具有双向信号传递的能力，因此其在该过程中的单独作用仍不清楚。为了更好地剖析各个作用，研究了一种具有减弱的 ephrinB2 反向信号的增殖性视网膜病变的小鼠模型。假设内皮细胞 ephrinB2 反向信号调节缺氧诱导的毛细血管发芽以及出生后视网膜微血管网络中新生血管丛的病理性形成。
具有减弱的 ephrinB2 反向信号（ephrinB2(lacZ/+)）的基因改造小鼠以及野生型（WT）对照，暴露于氧诱导的视网膜病变（OIR），这是一种增殖性视网膜病变的出生后模型。在疾病高峰期（出生后第 18 天），分析微血管网络以检查视网膜内再血管化、毛细血管发芽和病理性新生血管化反应。还评估了 EphB4 和磷酸化 ephrinB 蛋白在视网膜微血管上的表达模式。
与 WT 对照相比，ephrinB2(lacZ/+) 小鼠表现出缺氧诱导的再血管化减少（P≤0.04）和新生血管丛形成减少（P＜0.001）。与观察到的视网膜血管生成抑制相对应，ephrinB2(lacZ/+) 视网膜显示出更多的无终末毛细血管发芽尖端（P＜0.02）和内皮细胞丝状伪足过程（P=0.001）。在 WT 和 ephrinB2(lacZ/+) OIR 暴露的视网膜中，ephrinB 局限于内皮细胞，在包括新生血管丛和无终末毛细血管芽在内的血管生成血管过程中检测到表达。
EphrinB2 反向信号是视网膜血管生成过程中的关键调节因子，通过直接影响毛细血管发芽和内皮细胞丝状伪足形成来控制病理性视网膜血管生成。
