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A Uemura, M Hirashima, T Fujiwara, N Takakura, Y Honda, M Ogawa, SJ Wiegand, GD Yancopoulos, S-I Nishikawa; Ang1 Can Maintain Structural Integrity and Impose a Higher Order Architecture on Vascular Networks in the Complete Absence of Mural Cells . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1931.
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Purpose: Interactions between perivascular mural cells (MC) and endothelial cells (EC) via angiopoietin-1 (Ang1) and platelet-derived growth factor (PDGF)-B have been implicated both in vascular remodeling and maintenance of vascular integrity. In this study, we investigated the developing retinal vascular system as a suitable model for manipulating these processes. Methods: An antagonistic monoclonal antibody against PDGFR-ß (clone APB5) was injected intraperitoneally daily to neonatal mice. Litter mates injected with nonspecific rat immunoglobulins or with vehicle alone served as controls. Recombinant human Ang1 was injected into the vitreous cavity at P1, and again on days P4 and P7. Retinal vessels were analyzed by immnohistochemistry of wholemount retinal preparations or cryo sections using PECAM-1 as an EC marker and PDGFR-ß, desmin, and α-smooth muscle actin as MC markers. Retinal tissues were also analyzed by H&E staining of paraffin sections, BrdU incorporating assays, and transmission or scanning electron microscopy. Results: Most retinal vessels were covered by PDGFR-ß (+) MC, be it artery, vein or capillary. By systemic administration of APB5 during neonatal development, MC recruitment to retinal vessels was completely inhibited, resulting in a poorly remodeled and leaky vascular system. Utilizing this vascular network devoid of MC, which proved ideal for assessing the net activity of MC-derived molecules on the morphogenesis of endothelial networks, we show that Ang1 was sufficient to establish a hierarchical vasculature, comprising arteries, veins and capillaries in the complete absence of MC. Moreover, retinal edema and hemorrhage were also rescued by Ang1 administration. Conclusions: In addition to elucidating the role of Ang1 in retinal vascular development, our study also implies the potential of Ang1 as a new therapeutic modality for MC replacement in diseases such as diabetic retinopathies.
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