Abstract
Serum Response Factor (SRF) fulfills essential roles in post-natal retinal angiogenesis and adult neovascularization. These functions have been attributed to the recruitment by SRF of the cofactors Myocardin-Related Transcription Factors MRTF-A and -B, but not the Ternary Complex Factors (TCFs) Elk1 and Elk4. The role of the third TCF, Elk3, remained unknown. We generated a new Elk3 knockout mouse line and showed that Elk3 had specific, non-redundant functions in the retinal vasculature. In Elk3(−/−) mice, post-natal retinal angiogenesis was transiently delayed until P8, after which it proceeded normally. Interestingly, tortuous arteries developed in Elk3(−/−) mice from the age of four weeks, and persisted into late adulthood. Tortuous vessels have been observed in human pathologies, e.g. in ROP and FEVR. These human disorders were linked to altered activities of vascular endothelial growth factor (VEGF) in the affected eyes. However, in Elk3(−/−) mice, we did not observe any changes in VEGF or several other potential confounding factors, including mural cell coverage and blood pressure. Instead, concurrent with the post-natal transient delay of radial outgrowth and the formation of adult tortuous arteries, Elk3-dependent effects on the expression of Angiopoietin/Tie-signalling components were observed. Moreover, in vitro microvessel sprouting and microtube formation from P10 and adult aortic ring explants were reduced. Collectively, these results indicate that Elk3 has distinct roles in maintaining retinal artery integrity. The Elk3 knockout mouse is presented as a new animal model to study retinal artery tortuousity in mice and human patients.
Highlights
Angiogenesis is an important physiological process in which new blood vessels are generated by sprouting of existing ones
Generation of Elk3 deficient constitutive knockout mice Elk3 deficient mice were generated by homologous recombination and subsequent Cre-mediated deletion, as described in Materials and Methods and Figure S1
In this study we show that Elk3(2/2) mice display a dual retinal phenotype: (i) transient impairment in post-natal development of the superficial vascular plexus, paralleled by (ii) a lasting retinal arterial tortuousity in animals 4 weeks of age and older
Summary
Angiogenesis is an important physiological process in which new blood vessels are generated by sprouting of existing ones. Endothelial tip cells at the angiogenic front form numerous filopodia and guide vascularization, whereas stalk cells located behind tip cells are involved in proliferation and vessel extension [3]. Angiogenesis can be readily studied using the mouse retina. Many angiogenic events, such as endothelial cell (EC) proliferation, sprouting, recruitment of mural cells and maturation, occur post-natally and can be followed ex vivo on two-dimensional retinal flat-mount preparations [4]. Site-directed mutagenesis of the mouse genome can be used to identify genes involved in murine retinal vessel angiogenesis and physiology
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