Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae
Christine Weinl, … , Ralf H. Adams, Alfred Nordheim
Christine Weinl, … , Ralf H. Adams, Alfred Nordheim
Published April 8, 2013
Citation Information: J Clin Invest. 2013;123(5):2193-2206. https://doi.org/10.1172/JCI64201.
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Research Article Vascular biology Article has an altmetric score of 17

Endothelial SRF/MRTF ablation causes vascular disease phenotypes in murine retinae

Abstract

Retinal vessel homeostasis ensures normal ocular functions. Consequently, retinal hypovascularization and neovascularization, causing a lack and an excess of vessels, respectively, are hallmarks of human retinal pathology. We provide evidence that EC-specific genetic ablation of either the transcription factor SRF or its cofactors MRTF-A and MRTF-B, but not the SRF cofactors ELK1 or ELK4, cause retinal hypovascularization in the postnatal mouse eye. Inducible, EC-specific deficiency of SRF or MRTF-A/MRTF-B during postnatal angiogenesis impaired endothelial tip cell filopodia protrusion, resulting in incomplete formation of the retinal primary vascular plexus, absence of the deep plexi, and persistence of hyaloid vessels. All of these features are typical of human hypovascularization-related vitreoretinopathies, such as familial exudative vitreoretinopathies including Norrie disease. In contrast, conditional EC deletion of Srf in adult murine vessels elicited intraretinal neovascularization that was reminiscent of the age-related human pathologies retinal angiomatous proliferation and macular telangiectasia. These results indicate that angiogenic homeostasis is ensured by differential stage-specific functions of SRF target gene products in the developing versus the mature retinal vasculature and suggest that the actin-directed MRTF-SRF signaling axis could serve as a therapeutic target in the treatment of human vascular retinal diseases.

Authors

Christine Weinl, Heidemarie Riehle, Dongjeong Park, Christine Stritt, Susanne Beck, Gesine Huber, Hartwig Wolburg, Eric N. Olson, Mathias W. Seeliger, Ralf H. Adams, Alfred Nordheim

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Figure 4

Impaired regression of hyaloid vessels in SrfiECKO retinae.

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Impaired regression of hyaloid vessels in SrfiECKO retinae. (A) ILB4 s...
(A) ILB4 staining on retinal flat-mounts of P17 control and SrfiECKO retinae, displayed at lower (left; composite images, see Methods) and higher (middle and right) magnification. Flat-mount preparation used conditions to preserve hyaloid vessels. Red arrow indicates retarded angiogenic front; white arrows indicate persistent hyaloid vessels in SrfiECKO retinae. In the central area (middle), all capillary beds and no hyaloids were demonstrated in control retinae, whereas in SrfiECKO retinae, deep plexi were absent, but hyaloids were present. In the periphery (right), control retinae demonstrated complete vascularization, whereas outer avascular zones remained in SrfiECKO retinae, displaying distal microaneurysms and hyaloid vessels. (B) SLO angiography of SrfiECKO eyes revealed the course of hyaloid vessels, from their origin at the retinal center toward the avascular “target zone” in the periphery, via tracing on 3 different focal planes of the same eye (right, retinal surface; middle, intermediate level; left, just below the lens). Arrowheads denote hyaloid vessels, arrow denotes retinal vessel. Scale bars: 1 mm (A, left); 100 μm (A, middle and right).