Dataset Information

The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells.

ABSTRACT: Tie1 is a mechanistically poorly characterized endothelial cell (EC)-specific orphan receptor. Yet, Tie1 deletion is embryonic lethal and Tie1 has been implicated in critical vascular pathologies, including atherosclerosis and tumor angiogenesis. Here, we show that Tie1 does not function independently but exerts context-dependent effects on the related receptor Tie2. Tie1 was identified as an EC activation marker that is expressed during angiogenesis by a subset of angiogenic tip and remodeling stalk cells and downregulated in the adult quiescent vasculature. Functionally, Tie1 expression by angiogenic EC contributes to shaping the tip cell phenotype by negatively regulating Tie2 surface presentation. In contrast, Tie1 acts in remodeling stalk cells cooperatively to sustain Tie2 signaling. Collectively, our data support an interactive model of Tie1 and Tie2 function, in which dynamically regulated Tie1 versus Tie2 expression determines the net positive or negative effect of Tie1 on Tie2 signaling.

SUBMITTER: Savant S

PROVIDER: S-EPMC6309948 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Publications

The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells.

Savant Soniya S La Porta Silvia S Budnik Annika A Busch Katrin K Hu Junhao J Tisch Nathalie N Korn Claudia C Valls Aida Freire AF Benest Andrew V AV Terhardt Dorothee D Qu Xianghu X Adams Ralf H RH Baldwin H Scott HS Ruiz de Almodóvar Carmen C Rodewald Hans-Reimer HR Augustin Hellmut G HG

Cell reports 20150903 11

Tie1 is a mechanistically poorly characterized endothelial cell (EC)-specific orphan receptor. Yet, Tie1 deletion is embryonic lethal and Tie1 has been implicated in critical vascular pathologies, including atherosclerosis and tumor angiogenesis. Here, we show that Tie1 does not function independently but exerts context-dependent effects on the related receptor Tie2. Tie1 was identified as an EC activation marker that is expressed during angiogenesis by a subset of angiogenic tip and remodeling ...[more]

PMID: 26344773

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Project description:Angiogenesis is a highly dynamic morphogenesis process; however, surprisingly little is known about the timing of the different molecular processes involved. Although the role of the VEGF-notch-DLL4 signaling pathway has been established as essential for tip/stalk cell competition during sprouting, the speed and dynamic properties of the underlying process at the individual cell level has not been fully elucidated. In this study, using mathematical modeling we investigate how specific, biologically meaningful, local conditions around and within an individual cell can influence their unique tip/stalk phenotype switching kinetics. To this end we constructed an ordinary differential equation model of VEGF-notch-DLL4 signaling in a system of two, coupled endothelial cells (EC). Our studies reveal that at any given point in an angiogenic vessel the time it takes a cell to decide to take on a tip or stalk phenotype may be drastically different, and this asynchrony of tip/stalk cell decisions along vessels itself acts to speed up later competitions. We unexpectedly uncover intermediate "partial" yet stable states lying between the tip and stalk cell fates, and identify that internal cellular factors, such as NAD-dependent deacetylase sirtuin-1 (Sirt1) and Lunatic fringe 1 (Lfng1), can specifically determine the length of time a cell spends in these newly identified partial tip/stalk states. Importantly, the model predicts that these partial EC states can arise during normal angiogenesis, in particular during cell rearrangement in sprouts, providing a novel two-stage mechanism for rapid adaptive behavior to the cells highly dynamic environment. Overall, this study demonstrates that different factors (both internal and external to EC) can be used to modulate the speed of tip/stalk decisions, opening up new opportunities and challenges for future biological experiments and therapeutic targeting to manipulate vascular network topology, and our basic understanding of developmental/pathological angiogenesis.

Dataset Information

The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells.

Publications

The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells.

Similar Datasets

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