Neurite Mistargeting and Inverse Order of Intraretinal Vascular Plexus Formation Precede Subretinal Vascularization in Vldlr Mutant Mice.
Neurite Mistargeting and Inverse Order of Intraretinal Vascular Plexus Formation Precede Subretinal Vascularization in Vldlr Mutant Mice.
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DOI：
10.1371/journal.pone.0132013
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Junge HJ
中科院分区：
文献类型：
--
作者：
Johnson V;Xiang M;Chen Z;Junge HJ
在视网膜中，血管需要支持高代谢率，然而，不受控制的血管生长可导致视力受损和失明。视网膜下血管化（subretinal vascularization，SRV）是视网膜血管瘤性增生和增生性黄斑毛细血管扩张症的一种病理性血管生长。在这些疾病中，SRV起源于视网膜内的血管。我们使用Vldl受体（Vldlr）基因靶向破坏的小鼠作为模型来研究视网膜起源的SRV。我们发现，Vldlr mRNA强烈表达在神经视网膜，我们观察血管和神经元的表型Vldlr-/-小鼠。出乎意料的是，在该模型中，水平细胞（HC）神经突在SRV之前被错误定位，并且大多数血管病变与错误定位的神经突相关。在Foxn 4-/-小鼠中，缺乏HC并显示减少的无长突细胞（AC）数量，我们发现视网膜内毛细血管发育严重缺陷。然而，在Foxn 4-/-;Vldlr-/-小鼠中，SRV未被抑制，这揭示了血管病变形成不需要错误定位的HC神经突。在缺乏VLDLR的情况下，与正常发育相比，视网膜内毛细血管丛以相反的顺序形成，并且在这种早期缺陷之后，血管增殖增加。我们的结论是，在Vldlr-/-模型中的SRV与错误定位的神经突相关，并且在此之前，SRV改变了视网膜血管的发育。
In the retina blood vessels are required to support a high metabolic rate, however, uncontrolled vascular growth can lead to impaired vision and blindness. Subretinal vascularization (SRV), one type of pathological vessel growth, occurs in retinal angiomatous proliferation and proliferative macular telangiectasia. In these diseases SRV originates from blood vessels within the retina. We use mice with a targeted disruption in the Vldl-receptor (Vldlr) gene as a model to study SRV with retinal origin. We find that Vldlr mRNA is strongly expressed in the neuroretina, and we observe both vascular and neuronal phenotypes in Vldlr-/- mice. Unexpectedly, horizontal cell (HC) neurites are mistargeted prior to SRV in this model, and the majority of vascular lesions are associated with mistargeted neurites. In Foxn4-/- mice, which lack HCs and display reduced amacrine cell (AC) numbers, we find severe defects in intraretinal capillary development. However, SRV is not suppressed in Foxn4-/-;Vldlr-/- mice, which reveals that mistargeted HC neurites are not required for vascular lesion formation. In the absence of VLDLR, the intraretinal capillary plexuses form in an inverse order compared to normal development, and subsequent to this early defect, vascular proliferation is increased. We conclude that SRV in the Vldlr-/- model is associated with mistargeted neurites and that SRV is preceded by altered retinal vascular development.