Regulation of Foxo-1, the angiopoietin-2/Tie2 system and ADAMTS1 by shear stress

„Angioadaptation“ bezeichnet sowohl die Änderung der Anzahl von Blutgefäßen als auch den kontinuierlichen Umbau bestehender Gefäßnetzwerke an die Bedürfnisse des versorgten Gewebes. Die erfolgreiche Adaptation eines Gefäßnetzes äußert sich in der funktionsgerechten Sauerstoffversorgung eines Gewebes und durch die Optimierung der Strömungsmechanik zur Minimierung der Perfusionsenergie. Tatsächlich kann die Expression verschiedener vaskulärer Gene durch Sauerstoffpartialdruck, Dehnung (Stretch) und Schubspannung (Shear Stress) reguliert werden, wodurch auf zellulärer Ebene Rückkopplungsmechanismen im Sinne einer „Angioadaptation“ bestehen könnten. Unsere Publikationen konzentrierten sich auf die Identifikation von Mechanismen, welche eine Regulation der Angiogenese überwiegend durch Schubspannung ermöglichen. Das von Douglas Hanahan (Science. 1997 Jul 4;277(5322):48-50) etablierte Modell der Kontrolle von Vaskulogenese, Angiogenese, Maturation, Stabilisierung und Regression von Blutgefäßen durch ein Sauerstoffpartialdruck reguliertes Zusammenspiel von Ang1/Tie2 sowie VEGF konnte so unter Einbeziehung von ADAMTS1, Foxo-1 und der Schubspannung erweitert werden. Die Untersuchung endothelialer Gene, deren Expression durch Wandschubspannung geändert wird, führte uns darüber hinaus zu dem Transkriptionsfaktor ZNF580, welchem durch Beeinflussung von IL-8 eine Rolle sowohl bei der Angiogenese als auch bei der Atherogenese zuzuweisen ist.Angiogenesis is correlated with changes in hemodynamic forces, especially changes in wall shear stress. Our studies show that Foxo-1, Ang-2, Tie2 and ADAMTS1 are regulated by shear stress acting on endothelial cells. This will have implications for the regulation of different types of angiogenesis. In the last study we discovered ZNF580 as a novel factor in the regulation of IL-8 and monocyte arrest. We showed that high oxLDL/LDL-ratios are correlated with increased IL-8 serum levels in humans. Therefore it may be a potential target for intervention in atherosclerosis

Regulation of Foxo-1 and the angiopoietin-2/Tie2 system by shear stress

Transcription factor Foxo-1 can be inactivated via Akt-mediated phosphorylation. Since shear stress activates Akt, we determined whether Foxo-1 and the Foxo-1-dependent, angiogenesis-related Ang-2/Tie2-system are influenced by shear stress in endothelial cells. Expression of Foxo-1 and its target genes p27Kip1 and Ang-2 was decreased under shear stress (6dyn/cm(2), 24h), nuclear exclusion of Foxo-1 by phosphorylation increased. eNOS and Tie2 were upregulated. No effects on Ang-1 expression were detected. In conclusion, Foxo-1 and Ang-2/Tie2 are part of the molecular response to shear stress, which may regulate angiogenesis

Expression of ADAMTS1 in endothelial cells is induced by shear stress and suppressed in sprouting capillaries

ADAMTS1 inhibits capillary sprouting, and since capillary sprouts do not experience the shear stress caused by blood flow, this study undertook to clarify the relationship between shear stress and ADAMTS1. It was found that endothelial cells exposed to shear stress displayed a strong upregulation of ADAMTS1, dependent upon both the magnitude and duration of their exposure. Investigation of the underlying pathways demonstrated involvement of phospholipase C, phosphoinositide 3-kinase, and nitric oxide. Forkhead box protein O1 was identified as a likely inhibitor of the system, as its knockdown was followed by a slight increase in ADAMTS1 expression. In silico prediction displayed a transcriptional binding site for Forkhead box protein O1 in the promotor region of the ADAMTS1 gene, as well as sites for nuclear factor 1, SP1, and AP-1. The anti-angiogenic effects of ADAMTS1 were attributed to its cleavage of thrombospondin 1 into a 70-kDa fragment, and a significant enhancement of this fragment was indeed demonstrated by immunoblotting shear stress-treated cells. Accordingly, scratch wound closure displayed a slowdown in conditioned medium from shear stress-treated endothelial cells, an effect that could be completely blocked by a knockdown of thrombospondin 1 and partially blocked by a knockdown of ADAMTS1. Non-perfused capillary sprouts in rat mesenteries stained negative for ADAMTS1, while vessels in the microcirculation that had already experienced blood flow yielded the opposite results. The shear stress-dependent expression of ADAMTS1 in vitro was therefore also demonstrated in vivo and thereby confirmed as a mechanism connecting blood flow with the regulation of angiogenesis