Retinal vascular repair and neovascularization are not dependent on CX3CR1 signaling in a model of ischemic retinopathy.
Retinal vascular repair and neovascularization are not dependent on CX3CR1 signaling in a model of ischemic retinopathy.
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在缺血性视网膜病变模型中，视网膜血管修复和新生血管形成不依赖于 CX3CR1 信号传导。
DOI：
10.1016/j.exer.2008.12.013
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发表时间：
2009-06
影响因子：
3.4
通讯作者：
Wong, Wai T.
中科院分区：
文献类型：
--
作者：
Zhao, Lian;Ma, Wenxin;Fariss, Robert N.;Wong, Wai T.
缺血性视网膜新生血管的发生是许多视网膜疾病的常见机制。在最近的研究中，视网膜小胶质细胞已被证明可能通过与相关血管成分交换细胞信号来影响病理性新生血管形成。CX 3CR 1是一种特异性位于小胶质细胞上的趋化因子受体;其配体CX 3CL 1（也称为fractalkine或neurotactin）在体内和体外均显示促血管生成活性。发现CX 3CR 1信号在缺血性视网膜病变中的调节作用（如果有的话）将揭示小胶质细胞-血管相互作用的分子本质，并阐明未来治疗的潜在靶点。在这项研究中，我们通过诱导和比较CX 3CR 1信号被保留或消融的转基因小鼠的缺血性血管变化来研究这个问题。使用众所周知的氧诱导的视网膜病变（OIR）模型，我们诱导缺血性视网膜病变的转基因小鼠，其中CX 3CR 1基因已被替换为绿色荧光蛋白（GFP）和野生型对照。CX 3CR 1 +/+、CX 3CR 1 +/GFP和CX 3CR 1GFP/GFP转基因小鼠从出生后第7天（P）开始暴露于75%氧气5天，然后转移回室内空气。在P12和P17时，对血管修复和新生血管形成的程度以及视网膜小胶质细胞分布的相关变化进行定量，并在不同基因型的小鼠之间进行比较。还在石蜡切片中评价缺血后视网膜中的神经元损失。我们的研究结果表明：（1）出生后第一周视网膜中的正常血管、小胶质细胞和神经元发育不需要CX 3CR 1信号传导，（2）缺血后视网膜血管修复和新血管形成的过程在有和没有CX 3CR 1信号传导的情况下类似地发生，（3）视网膜中的小胶质细胞再分布及其与同时发生的血管成分的关联不依赖于CX 3CR 1，（4）CX 3CR 1不影响缺血后视网膜神经细胞的丢失程度。总之，我们的研究结果表明，在缺血性视网膜病变动物模型中，小胶质细胞和血管成分之间交换的调节信号不太可能涉及CX 3CR 1。这些结果对病理性新血管形成的治疗方法具有启示，病理性新血管形成涉及一般的趋化因子信号传导的调节，以及具体的CX 3CR 1信号传导的调节。
Proliferative retinal neovascularization occurring in response to ischemia is a common mechanism underlying many retinal diseases. In recent studies, retinal microglia have been shown to influence pathological neovascularization, likely through an exchange of cellular signals with associated vascular elements. CX3CR1 is a chemokine receptor located specifically on microglia; its ligand, CX3CL1 (also known as fractalkine or neurotactin) displays pro-angiogenic activity both in in vivo and in vitro. Discovering the regulatory role, if any, that CX3CR1 signaling may have in ischemic retinopathy will shed light on the molecular nature of microglial-vascular interactions and clarify potential targets for future therapy. In this study, we examined this question by inducing and comparing ischemic vascular changes in transgenic mice in which CX3CR1 signaling is either preserved or ablated. Using a well-known oxygen-induced retinopathy (OIR) model, we induced ischemic retinopathy in transgenic mice in which the gene for CX3CR1 has been replaced by green fluorescent protein (GFP) and their wild type controls. CX3CR1+/+, CX3CR1+/GFP, and CX3CR1GFP/GFP transgenic mice were exposed to 75% oxygen for 5 days starting from postnatal day (P) 7, and then transferred back to room air. At P12 and P17, the extents of vascular repair and neovascularization, and associated changes in retinal microglia distribution, were quantified and compared between mice of different genotypes. Neuronal loss in the retina following ischemia was also evaluated in paraffin sections. Our results show that: (1) CX3CR1 signaling is not required for normal vascular, microglial, and neuronal development in the retina in the first postnatal week, (2) the processes of retinal vascular repair and neovascularization following ischemia occur similarly with and without CX3CR1 signaling, (3) microglia redistribution in the retina and their association with vascular elements occurring concurrently is independent of CX3CR1, and (4) CX3CR1 does not influence the extent of neuronal cell loss in the retina following ischemia. Taken together, our findings indicate that the regulatory signals exchanged between microglia and vascular elements in the ischemic retinopathy animal model are unlikely to involve CX3CR1. These results have implications on therapeutic approaches to, pathological neovascularization involving the modulation of chemokine signaling in general, and the regulation of CX3CR1 signaling specifically.
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