The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells.
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.
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany; Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Soniya
S
Savant
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.
Silvia
S
La Porta
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.
Annika
A
Budnik
Division of Cellular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany.
Katrin
K
Busch
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.
Junhao
J
Hu
Biochemistry Center BZH, Heidelberg University, 69120 Heidelberg, Germany.
Nathalie
N
Tisch
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.
Claudia
C
Korn
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.
Aida Freire
AF
Valls
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.
Andrew V
AV
Benest
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany.
Dorothee
D
Terhardt
Division of Cardiology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Xianghu
X
Qu
Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, 48145 Münster, Germany; Faculty of Medicine, University of Münster, 48145 Münster, Germany.
Ralf H
RH
Adams
Division of Cardiology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
H Scott
HS
Baldwin
Biochemistry Center BZH, Heidelberg University, 69120 Heidelberg, Germany.
Carmen
C
Ruiz de Almodóvar
Division of Cellular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany.
Hans-Reimer
HR
Rodewald
Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany; Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Electronic address: augustin@angiogenese.de.
Hellmut G
HG
Augustin
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000502:physiology; D042810:Receptor, TIE-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012171:Retinal Vessels / Q000502:physiology; D015398:Signal Transduction; D066253:Vascular Remodeling / Q000502:physiology*
D042810:Receptor, TIE-1; D042787:Receptor, TIE-2