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Zusammenfassung:
Serum Response Factor (SRF) is a ubiquitously expressed transcription factor, that regulates the transcrip- tion of about 1000 genes. Endothelial cell specific deletion of SRF has been shown to cause the formation of hemorrhages in the neonatal murine brain and microaneurysms in the retina, but its physiological role in mural cells (MCs) remains unknown. MCs wrap around blood vessels and play important roles in angiogene- sis, vessel stabilization and homeostasis. They are essential to maintain the integrity of the blood brain barrier and play important roles in numerous diseases. To investigate the role of SRF in MCs, we established Srf-flex- 1::Pdgfbr-CreERT2 mice and studied the consequences of MC-specific SRF deletion in the postnatal mouse retina. Retinal angiogenesis, Microscopy, RNAseq We found that MCs lacking Srf adopt an abnormal morphology, lose the expression of smooth muscle actin and fail to properly co-migrate with angiogenic vascular sprouts. Blood vessels at the sprouting front remain deprived from MCs, become dilated and appear to lose their barrier properties, as red blood cells extravasate in the surrounding tissue. Most interestingly, however, from postnatal day 12 (P12), these mice also develop ar- terio-venous shunts which become increasingly severe with age. Interestingly, those malformations resemble arterio-venous malformations described in animal models of Hereditary Hemorrhagic Telangiectasia (HHT), but develop substantially later. MCs that lack SRF accumulate around the malformed vessels, while overall MC coverage in the adjacent unaffected vasculature becomes reduced. In vitro experiments with primary isolated MCs suggest that a lack of Srf leads to cytoskeletal defects and a failure of MCs to migrate. Taken together, our data suggest that, in the absence of Srf, MCs acquire a disease-promoting competence which is not phenocopied by MC ablation. Our ongoing studies now aim to investigate the involvement of MCs in the development of vascular malformations such as in HHT.
