Dorrell Michael I, Aguilar Edith, Friedlander Martin
Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Invest Ophthalmol Vis Sci. 2002 Nov;43(11):3500-10.
A neonatal mouse retina developmental model was used to study endothelial cell guidance and subsequent formation of vascular patterns. Since most diseases that cause catastrophic loss of vision do so as a result of abnormal ocular angiogenesis, a better understanding of events regulating normal retinal vascular growth may provide insight into pathologic angiogenesis.
Development of the retinal vasculature at various postnatal and embryonic time points was analyzed by collagen IV immunohistochemistry and staining with isolectin Griffonia simplicifolia. GFAP-GFP transgenic mice were used to evaluate the relationship between developing vessels and retinal glial cells. Immunolocalization of R-cadherin and intravitreous injection of R-cadherin-specific antibodies was performed to determine the role of R-cadherin during patterning of the superficial and deep retinal vascular plexuses.
The characteristic honeycomb pattern of vessel formation observed in the superficial layer is a result of endothelial cell migration over a preexisting astrocytic template. Filopodial extensions associate with underlying astrocytes by protruding from the tips of endothelial cells at the migrating vascular front. Branching of vessels in the primary vascular plexus, as well as appropriate localization of the deep vascular network is mediated by R-cadherin, an adhesion molecule known to be involved in neuronal cell guidance. Injection of antibodies directed against R-cadherin prevents the normally extensive collateralization observed during formation of the superficial network. Injection of anti-R cadherin antibodies also dramatically affects vessels of the deep network. These vessels migrate beyond the normal turning point, penetrating into the deeper photoreceptor layer.
. These studies suggest that angiogenesis and formation of vascular patterns in the retina may use many of the same developmental cues used by neurons in both the central and peripheral nervous systems. Furthermore, retinal vascular endothelial cell guidance mediated by filopodial extensions and neuronal guidance cues may represent a novel conceptual framework within which to study the establishment of vascular patterns in a variety of angiogenic systems.
利用新生小鼠视网膜发育模型研究内皮细胞导向及随后血管模式的形成。由于大多数导致视力灾难性丧失的疾病是由眼部血管生成异常所致，因此更好地了解调节正常视网膜血管生长的事件可能有助于深入了解病理性血管生成。
通过IV型胶原免疫组织化学和用简并刀豆球蛋白进行染色，分析出生后和胚胎期不同时间点视网膜血管系统的发育情况。利用GFAP-GFP转基因小鼠评估发育中的血管与视网膜神经胶质细胞之间的关系。进行R-钙黏蛋白的免疫定位和玻璃体内注射R-钙黏蛋白特异性抗体，以确定R-钙黏蛋白在视网膜浅、深血管丛模式形成过程中的作用。
在表层观察到的特征性蜂窝状血管形成模式是内皮细胞在预先存在的星形胶质细胞模板上迁移的结果。丝状伪足延伸通过从迁移血管前端的内皮细胞尖端伸出而与下方的星形胶质细胞相关联。初级血管丛中的血管分支以及深部血管网络的适当定位由R-钙黏蛋白介导，R-钙黏蛋白是一种已知参与神经元细胞导向的黏附分子。注射针对R-钙黏蛋白的抗体可阻止在浅表网络形成过程中正常出现的广泛侧支化。注射抗R-钙黏蛋白抗体也会显著影响深部网络的血管。这些血管迁移到正常转折点之外，穿透到更深的光感受器层。
这些研究表明，视网膜血管生成和血管模式的形成可能利用了中枢和外周神经系统中神经元所使用的许多相同的发育线索。此外，由丝状伪足延伸和神经元导向线索介导的视网膜血管内皮细胞导向可能代表了一个新的概念框架，可用于研究各种血管生成系统中血管模式的建立。
