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

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 3

Vascular abnormalities in SRF-depleted retinae at P17.

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Vascular abnormalities in SRF-depleted retinae at P17. (A) SLO FLA of P1...
(A) SLO FLA of P17 control and SrfiECKO mice. An enlarged view of the middle panel is shown at right (enlarged ×3-fold). (B) ILB4 staining on retinal flat-mounts after SLO imaging (flat-mount preparation included removal of hyaloid vessels). Images are composites (see Methods). Distal microaneurysms of different sizes (white arrows, small; arrowheads, large), as visualized in vivo in A, were also observed by ILB4 staining (see higher-magnification view at right). Red arrow indicates recessed angiogenic front of the primary plexus in SrfiECKO retinae. (C) Visualization of microaneurysms in SrfiECKO retinae by OCT (right) and, subsequently, by H&E staining of paraffin sections (left and middle). In SrfiECKO retinae, erythrocyte-filled microaneurysms were present (white arrows) that caused local displacement of other layers. OCT confirmed this finding to be similarly identifiable in vivo in SrfiECKO retinae (black arrows indicate distal microaneurysms). GCL, ganglion cell layer. Scale bars: 1 mm (B, left and middle); 100 μm (B, right); 25 μm (C).