The retina is a highly vascularized tissue, but too much or too little vascularization can lead to visual impairment and diseases such as familial exudative vitreoretinopathy or macular degeneration. Christine Weinl and colleagues identified the transcription factor SRF and its cofactors MRTF-A and MRTF-B as critical regulators of vascularization in the postnatal mouse eye. They developed transgenic mice in which expression of SRF could be blocked at different points in development. Weinl and colleagues used a confocal scanning laser opthalmoscope (SLO) and fluorescein angiography, which highlights blood vessels, to examine the retinal vasculature of wild type (top left) and Srf-depleted mice (top middle and top right). The bottom panels of the accompanying image show retinal flat mounts from wild type (bottom left) and Srf-depleted mice (bottom middle, bottom right) stained for ILB4, a marker of the retinal primary plexus, which forms the eye's blood supply. Loss of vascular Srf in adult mice led to the formation of microaneurysms and excess blood vessel formation similar to human retinal diseases such as retinal angiomatous proliferation and macular telangiectasia. These studies demonstrate that SRF plays an integral role in the development and homeostasis or the retinal vasculature and suggest that SRF could potentially serve as a therapeutic target in human retinal diseases.
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
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