Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling

Felcht, Moritz; Luck, Robert; Schering, Alexander; Seidel, Philipp; Srivastava, Kshitij; Hu, Junhao; Bartol, Arne; Kienast, Yvonne; Vettel, Christiane; Loos, Elias K.; Kutschera, Simone; Bartels, Susanne; Appak, Sıla; Besemfelder, Eva; Terhardt, Dorothee; Chavakis, Emmanouil; Wieland, Thomas; Klein, Christian; Thomas, Markus; Uemura, Akiyoshi; Goerdt, Sergij; Augustin, Hellmut G.

doi:10.1172/jci58832

Cited by 400 publications

(382 citation statements)

References 51 publications

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“…Considering the recent finding that YAP plays a key role in cellular mechanotransduction, it is not surprising that ANG-2 is regulated by YAP in ECs. A recent report showed that ANG-2 transcript levels are inversely correlated with EC density in vitro 22 , thus supporting our hypothesis that ANG-2 may be regulated by cell-cell contact-mediated YAP phosphorylation. Although it is still under investigation how YAP transcriptionally regulates ANG-2, our present study provides new insights into the regulatory mechanism of ANG-2 expression in ECs.…”

Section: Discussionsupporting

confidence: 90%

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Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

et al. 2015

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Angiogenesis is regulated by the dynamic interaction between endothelial cells (ECs).Hippo-Yes-associated protein (YAP) signalling has emerged as a key pathway that controls organ size and tissue growth by mediating cell contact inhibition. However, the role of YAP in EC has not been defined yet. Here, we show expression of YAP in the developing front of mouse retinal vessels. YAP subcellular localization, phosphorylation and activity are regulated by VE-cadherin-mediated-EC contacts. This VE-cadherin-dependent YAP phosphorylation requires phosphoinositide 3-kinase-Akt activation. We further identify angiopoietin-2 (ANG-2) as a potential transcriptional target of YAP in regulating angiogenic activity of EC in vitro and in vivo. Overexpression of YAP-active form in EC enhances angiogenic sprouting, and this effect is blocked by ANG-2 depletion or soluble Tie-2 treatment. These findings implicate YAP as a critical regulator in angiogenesis and provide new insights into the mechanism coordinating junctional stability and angiogenic activation of ECs.

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Section: Discussionsupporting

confidence: 90%

“…7b-d). Similar patterns were also observed in ANG-2-neutralizing antibody-injected mice 22 . Consistently, the mRNA expression of ANG-2 was significantly reduced in Yap siRNAinjected mouse retinas (Fig.…”

Section: Yap Is Expressed In the Ecs Of The Neovascular Regionsupporting

confidence: 79%

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

et al. 2015

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“…Various barrier-stabilizing mediators activate Rac1, including sphingosine 1-phosphate (S1P) and angiopoietins. [58][59][60] Barrier-protective cAMP signaling activates Rac1 indirectly via the RasGTPase Rap1. 61,62 In addition, Rac1 activation downstream of thrombin promotes reassembly of cell-cell junctions during the endothelial barrier recovery phase.…”

Section: Endothelial Adherens Junction Control By Rho Gtpasesmentioning

confidence: 99%

Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

Buul

Timmerman

2016

Small GTPases

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VE-cadherin-based cell-cell junctions form the major restrictive barrier of the endothelium to plasma proteins and blood cells. The function of VE-cadherin and the actin cytoskeleton are intimately linked. Vascular permeability factors and adherent leukocytes signal through small Rho GTPases to tightly regulate actin cytoskeletal rearrangements in order to open and re-assemble endothelial cell-cell junctions in a rapid and controlled manner. The Rho GTPases are activated by guanine nucleotide exchange factors (GEFs), conferring specificity and context-dependent control of cell-cell junctions. Although the molecular mechanisms that couple cadherins to actin filaments are beginning to be elucidated, specific stimulus-dependent regulation of the actin cytoskeleton at VEcadherin-based junctions remains unexplained. Accumulating evidence has suggested that depending on the vascular permeability factor and on the subcellular localization of GEFs, cell-cell junction dynamics and organization are differentially regulated by one specific Rho GTPase. In this Commentary, we focus on new insights how the junctional actin cytoskeleton is specifically and locally regulated by Rho GTPases and GEFs in the endothelium.

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“…First, Tie2 phosphorylation is tightly controlled by the interplay of several proteins: a paralogous receptor, Tie1; a tyrosine phosphatase, vascular endothelial-protein tyrosine phosphatase (VE-PTP); and two secreted ligands, angiopoietin (Angpt)-1 and Angpt-2, the latter of which can act as an agonist, partial agonist, or antagonist depending upon context (1)(2)(3)(4)(5)(6). Second, unlike classic growth factor receptors, Tie2 is heavily expressed and phosphorylated throughout the quiescent adult vasculature (7), suggesting that Tie2 signaling has one or more roles in vascular maintenance.…”

mentioning

confidence: 99%

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

Ghosh

David

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.Tie2 | endothelium | infection | angiopoietin | permeability

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Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling

Cited by 400 publications

References 51 publications

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

Small Rho GTPase-mediated actin dynamics at endothelial adherens junctions

Gene control of tyrosine kinase TIE2 and vascular manifestations of infections

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