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.
View: Text | PDF
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

×

Figure 1

EC depletion of SRF impairs angiogenesis in P6 murine retinal development.

Options: View larger image (or click on image) Download as PowerPoint
EC depletion of SRF impairs angiogenesis in P6 murine retinal developmen...
(A) ILB4-stained retinal flat-mounts of P6 control and SrfiECKO mice. Top: Progression of angiogenic front. Red arrow indicates recessed angiogenic front of the primary plexus in SrfiECKO retinae. Images are composites (see Methods). Middle: Vessel density between artery (A) and vein (V). Bottom: Sprout morphology. White arrows indicate filopodia; red asterisks highlight abnormal morphologies of SrfiECKO tip cells. (B) Quantitation of retinal area covered by blood vessels (radial outgrowth), expressed as percentage of control. n = 6 retinae. (C and D) Quantitation of (C) branch points in a field of view (A, middle, white boxes) and (D) abnormal sprouts. n = 4 retinae. (E and F) Quantitation of (E) filopodial number per sprout and (F) mean length of individual filopodia. n = 30 sprouts (control); 39 sprouts (SrfiECKO). (G) Retinal flat-mounts of P8 mice lacking the double-fluorescent mTmG Cre reporter, Srfflex1/flex1Cdh5(PAC)-CreERT2mTmG mice (SrfiECKOTG), and control Srfflex1/WTCdh5(PAC)-CreERT2mTmG mice. Shown are red fluorescent channel (mTomato) and GFP (mGFP) signals of the same retinae, the latter being obtained upon CreERT2 activation by intragastric tamoxifen injection (+ tamox). Red arrow indicates recessed angiogenic front of the primary plexus in Srfflex1/flex1Cdh5(PAC)-CreERT2mTmG retinae. Images are composites (see Methods). Scale bars: 1 mm (A, top, and G); 50 μm (A, middle); 15 μm (A, bottom). *P < 0.05, **P < 0.01, ***P < 0.001 vs. respective control.