Background— The adaptive growth of blood vessels is an important protective mechanism in cardiovascular disease. However, the underlying regulatory mechanisms of this process are only partly understood. Recently, small endogenous RNAs (microRNAs [miRNAs]) were found to play an important role in embryonic and postnatal vascular development. Here, we used miRNA transcriptome analysis after induction of hind-limb ischemia in mice to screen for miRNAs involved in adaptive blood vessel growth following arterial occlusion. Methods and Results— Using miRNA arrays, we explored the miRNA expression profile during adaptive neovascularization. We describe specific changes in miRNA expression patterns and show that miRNA-100 is significantly downregulated after induction of hind-limb ischemia in mice. Our data demonstrate that miR-100 modulates proliferation, tube formation, and sprouting activity of endothelial cells and migration of vascular smooth muscle cells and functions as an endogenous repressor of the serine/threonine protein kinase mammalian target of rapamycin (mTOR). Whereas miR-100 inhibition increased mTOR levels in endothelial cells, overexpression of miR-100 reduced mTOR expression and consequently attenuated cellular proliferation. Supporting this notion, overexpression of an mTOR construct lacking the miRNA binding site rescued the inhibitory effect of miR-100 on cell proliferation. Accordingly, miR-100 inhibition by specific antagomirs in vivo stimulated angiogenesis and resulted in functional improvement of perfusion after femoral artery occlusion in mice. In contrast, treatment with the mTOR inhibitor rapamycin had the opposite effect. Conclusions— Our data demonstrate that miR-100 has an antiangiogenic function and represses mTOR signaling in endothelial and vascular smooth muscle cells. Inhibition of miR-100 could be a novel approach for the modulation of blood vessel growth and other mTOR-dependent processes.
Forkhead box (Fox) transcription factors are important regulators of cardiovascular development and several Fox-proteins have recently been shown to modulate embryonic and post-natal angiogenesis. However, the role of the FoxP subfamily, which is highly expressed in cardiovascular tissue, has not been investigated so far. Here, we show that the transcription factor FoxP1 is the highest expressed FoxP-protein in endothelial cells and that it is upregulated at the site of neovascularization during hindlimb ischemia in mice. Silencing of FoxP1 results in a strong inhibition of proliferation, tube formation and migration of cultured endothelial cells. Accordingly, knockdown of FoxP1 in zebrafish was followed by a disruption of intersomitic vascular formation. Using gene expression profiling, we show that FoxP1 induces a specific change of the endothelial transcriptome and functions as a suppressor of semaphorin 5B, which has previously been described as a neuronal inhibitory factor. Our findings now demonstrate that semaphorin 5B also acts as a FoxP1- dependent suppressor of endothelial cell proliferation, migration and sprouting, mediating the effects of FoxP1. In summary, our data indicate that the transcription factor FoxP1 is essential for the angiogenic function of endothelial cells and functions as a suppressor of the inhibitory guidance cue semaphorin 5B, suggesting an important function of FoxP1 in the regulation of neovascularization.
Zusammenfassung Hintergrund Das neue, pandemische Coronavirus SARS-CoV-2 und die damit einhergehende Erkrankung COVID-19 (Coronavirus Disease 2019) stellt die medizinischen Versorgungssysteme vor große Herausforderungen. Die vorliegende Arbeit fasst die Strategie, Organisation und Maßnahmen der COVID-Taskforce des Universitätsklinikums Freiburg zusammen und berichtet über Erfahrungen und Behandlungsergebnisse von der Versorgung der ersten 115 COVID-19-Patienten. Methoden Retrospektive, narrative Prozessbeschreibung und -analyse des Zeitraums Ende Januar bis Anfang April 2020, durchgeführt unter Mitwirken der beteiligten Departments, Kliniken und Institute des Universitätsklinikums Freiburg. Ergänzend erfolgte eine retrospektive Beobachtungsstudie mit deskriptiver statistischer Auswertung der epidemiologischen und klinischen Daten aller bis 31. März 2020 hospitalisierten COVID-19-Patienten. Ergebnisse Durch eine interdisziplinär zusammengesetzte Taskforce Coronavirus wurden Maßnahmen in den Bereichen ambulante Testung und Beratung, Separierung der Patientenströme sowie Eskalation der Versorgungskapazitäten auf Normal- und Intensivstationen im Sinne eines dynamischen Stufenmodells angeregt und umgesetzt. Die Versorgung der ersten 115 Patienten gelang somit ohne Entstehung von Engpässen. Diskussion Durch Zusammenwirken sämtlicher Disziplinen und Abteilungen des Universitätsklinikums Freiburg konnte eine adäquate Versorgung von COVID-19-Patienten sichergestellt und die Handlungsfähigkeit des Klinikums in der aktuellen Ausbruchsituation erhalten werden.
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