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

• Published in: Cell reports (Cambridge) 2015-09, Vol.12 (11), p.1761-1773
• Main Authors: Savant, Soniya, La Porta, Silvia, Budnik, Annika, Busch, Katrin, Hu, Junhao, Tisch, Nathalie, Korn, Claudia, Valls, Aida Freire, Benest, Andrew V., Terhardt, Dorothee, Qu, Xianghu, Adams, Ralf H., Baldwin, H. Scott, Ruiz de Almodóvar, Carmen, Rodewald, Hans-Reimer, Augustin, Hellmut G.
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - physiology; Cells, Cultured; Embryonic Stem Cells - cytology; Endothelial Cells - cytology; Endothelial Cells - enzymology; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic - physiology; Receptor, TIE-1 - genetics; Receptor, TIE-1 - metabolism; Receptor, TIE-1 - physiology; Receptor, TIE-2 - genetics; Receptor, TIE-2 - metabolism; Receptor, TIE-2 - physiology; Retinal Vessels - physiology; Signal Transduction; Vascular Remodeling - physiology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2015.08.024

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. [Display omitted] •Tie1 is expressed by a subset of angiogenic and remodeling endothelial cells•In tip cells, Tie1 counter-regulates Tie2 cell surface presentation•In remodeling endothelial cells, Tie1 sustains Tie2 signaling and cell survival•The functional coordination of Tie1-Tie2 is required for angiogenesis and remodeling Using endothelial-specific conditional knockout mice, Savant et al. demonstrate a context-dependent modulatory function of Tie1 on Tie2 signaling. Tie1 is dynamically expressed by subset of endothelial cells in the postnatal retina. Dynamic regulation of Tie1 and Tie2 is required during angiogenesis and vascular remodeling.