Although the response of endothelial cells to the disturbed blood flow in the vicinity of atherosclerotic lesions is known to be distinct from that elicited by nonatherogenic laminar flow, the mechanisms involved are poorly understood. Our initial studies confirmed that expression of the endothelial receptor tyrosine kinase Tie1 was evident at regions of atherogenic flow in mature animals. We therefore hypothesized that Tie1 plays a role in the endothelial response to atherogenic shear stress. Consistent with this, we found that Tie1+/– mice bred to the apoE-deficient background displayed a 35% reduction in atherosclerosis relative to Tie1+/+;Apoe–/– mice. Since deletion of Tie1 results in embryonic lethality secondary to vascular dysfunction, we used conditional and inducible mutagenesis to study the effect of endothelial-specific Tie1 attenuation on atherogenesis in Apoe–/– mice and found a dose-dependent decrease in atherosclerotic lesions. Analysis of primary aortic endothelial cells indicated that atheroprotective laminar flow decreased Tie1 expression in vitro. Attenuation of Tie1 was associated with an increase in eNOS expression and Tie2 phosphorylation. In addition, Tie1 attenuation increased IkBα expression while decreasing ICAM levels. In summary, we have found that shear stress conditions that modulate atherogenic events also regulate Tie1 expression. Therefore, Tie1 may play a novel proinflammatory role in atherosclerosis.
Kel Vin Woo, Xianghu Qu, Vladimir R. Babaev, MacRae F. Linton, Raul J. Guzman, Sergio Fazio, H. Scott Baldwin
Title and authors | Publication | Year |
---|---|---|
Mycobacteria Exploit Host GPR84 to Dampen Pro-Inflammatory Responses and Promote Infection in Macrophages
Wumaier R, Zhang K, Zhou J, Wen Z, Chen Z, Luo G, Wang H, Qin J, Du B, Ren H, Song Y, Gao Q, Yan B |
Microorganisms | 2025 |
Loss-of-function mutations of the TIE1 receptor tyrosine kinase cause congenital and late-onset primary lymphedema
Pascal Brouillard, Aino Murtomäki, Veli-Matti Leppänen, Marko Hyytiäinen, Sandrine Mestre, Lucas Potier, Laurence Boon, Nicole Revencu, Arin Greene, Miia Salo, Reetta Hinttala, Lauri Eklund, Isabelle Quéré, Kari Alitalo, Miikka Vikkula |
Journal of Clinical Investigation | 2024 |
Mechanosensory entities and functionality of endothelial cells.
Mierke CT, Mierke CT |
Frontiers in cell and developmental biology | 2024 |
Vascular mechanotransduction
Davis MJ, Earley S, Li YS, Chien S |
Physiological reviews | 2023 |
FLI1 regulates radiotherapy resistance in nasopharyngeal carcinoma through TIE1-mediated PI3K/AKT signaling pathway
Chen E, Huang J, Chen M, Wu J, Ouyang P, Wang X, Shi D, Liu Z, Zhu W, Sun H, Yang S, Zhang B, Deng W, Qiu H, Xie F |
Journal of Translational Medicine | 2023 |
A machine-learning algorithm integrating baseline serum proteomic signatures predicts exercise responsiveness in overweight males with prediabetes.
Diaz-Canestro C, Chen J, Liu Y, Han H, Wang Y, Honoré E, Lee CH, Lam KSL, Tse MA, Xu A |
Cell reports. Medicine | 2023 |
The angiopoietin receptor Tie2 is atheroprotective in arterial endothelium
Anisimov A, Fang S, Hemanthakumar KA, Örd T, van Avondt K, Chevre R, Toropainen A, Singha P, Gilani H, Nguyen SD, Karaman S, Korhonen EA, Adams RH, Augustin HG, Öörni K, Soehnlein O, Kaikkonen MU, Alitalo K |
2023 | |
The emerging Janus face of SVEP1 in development and disease
Elenbaas JS, Jung IH, Coler-Reilly A, Lee PC, Alisio A, Stitziel NO |
Trends in Molecular Medicine | 2023 |
Laminar shear stress inhibits inflammation by activating autophagy in human aortic endothelial cells through HMGB1 nuclear translocation
Q Meng, L Pu, M Qi, S Li, B Sun, Y Wang, B Liu, F Li |
2022 | |
Pattern of tamoxifen-induced Tie2 deletion in endothelial cells in mature blood vessels using endo SCL-Cre-ERT transgenic mice
Zwiers PJ, Jongman RM, Kuiper T, Moser J, Stan RV, Göthert JR, van Meurs M, Popa ER, Molema G |
PloS one | 2022 |
Single-Cell Analysis Uncovers Osteoblast Factor Growth Differentiation Factor 10 as Mediator of Vascular Smooth Muscle Cell Phenotypic Modulation Associated with Plaque Rupture in Human Carotid Artery Disease.
Brandt KJ, Burger F, Baptista D, Roth A, Fernandes da Silva R, Montecucco F, Mach F, Miteva K |
International journal of molecular sciences | 2022 |
Nuclear Mechanosensation and Mechanotransduction in Vascular Cells
Salvador J, Iruela-Arispe ML |
Frontiers in Cell and Developmental Biology | 2022 |
p38α in macrophages aggravates arterial endothelium injury by releasing IL-6 through phosphorylating megakaryocytic leukemia 1
M Zhang, J Gao, X Zhao, M Zhao, D Ma, X Zhang, D Tian, B Pan, X Yan, J Wu, X Meng, H Yin, L Zheng |
Redox Biology | 2021 |
Early Aberrant Angiogenesis Due to Elastic Fiber Fragmentation in Aortic Valve Disease
RB Hinton, AL Juraszek, AM Opoka, BJ Landis, JM Smith, RP Mecham, KE Bove |
Journal of Cardiovascular Development and Disease | 2021 |
A systems biology model of junctional localization and downstream signaling of the Ang–Tie signaling pathway
Y Zhang, CD Kontos, BH Annex, AS Popel |
npj Systems Biology and Applications | 2021 |
Insight into the Role of Angiopoietins in Ageing-Associated Diseases
S Hayashi, H Rakugi, R Morishita |
Cells | 2020 |
An evaluation of the tumour endothelial marker CLEC14A as a therapeutic target in solid tumours
J Robinson, K Whitworth, E Jinks, Z Nagy, R Bicknell, SP Lee |
The Journal of Pathology: Clinical Research | 2020 |
A new Tie1 targeted antibody blocks tumor cell extravasation and metastasis
KA Khan, RS Kerbel |
EMBO Molecular Medicine | 2020 |
Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication
JB Funcke, PE Scherer |
Journal of lipid research | 2019 |
Angiopoietin-Tie Signaling Pathway in Endothelial Cells: A Computational Model
Y Zhang, CD Kontos, BH Annex, AS Popel |
iScience | 2019 |
Loss of flow responsive Tie1 results in Impaired Aortic valve remodeling
X Qu, K Violette, MK Sewell-Loftin, J Soslow, LS Saint-Jean, RB Hinton, WD Merryman, HS Baldwin |
Developmental Biology | 2019 |
Anti-angiogenic Targets: Angiopoietin and Angiopoietin Receptors
Kiss EA, Saharinen P |
Tumor Angiogenesis | 2019 |
Endothelial Tie1 regulates tumor angiogenesis, vascular abnormalization and metastatic dissemination
Silvia La Porta, Lise Roth, Mahak Singhal, Carolin Mogler, Carleen Spegg, Benjamin Schieb, Xianghu Qu, Ralf H. Adams, H. Scott Baldwin, Soniya Savant, Hellmut Augustin |
Journal of Clinical Investigation | 2018 |
Development of the renal vasculature
T Mohamed, ML Sequeira-Lopez |
Seminars in Cell & Developmental Biology | 2018 |
Endothelial Activation: The Ang/Tie Axis in Sepsis
A Leligdowicz, M Richard-Greenblatt, J Wright, VM Crowley, KC Kain |
Frontiers in immunology | 2018 |
Angiogenesis in the atherosclerotic plaque
C Camaré, M Pucelle, A Nègre-Salvayre, R Salvayre |
Redox Biology | 2017 |
Structural basis of Tie2 activation and Tie2/Tie1 heterodimerization
VM Leppänen, P Saharinen, K Alitalo |
Proceedings of the National Academy of Sciences | 2017 |
Elevated expression of Tie1 is accompanied by acquisition of cancer stemness properties in colorectal cancer
M Torigata, D Yamakawa, N Takakura |
Cancer Medicine | 2017 |
Therapeutic targeting of the angiopoietin–TIE pathway
P Saharinen, L Eklund, K Alitalo |
Nature Reviews Drug Discovery | 2017 |
Tie1: An orphan receptor provides context for angiopoietin-2/Tie2 signaling
Sarah Mueller, Christopher D. Kontos |
Journal of Clinical Investigation | 2016 |
Tie1 controls angiopoietin function in vascular remodeling and inflammation
Emilia Anne Korhonen, Anita Lampinen, Hemant Giri, Andrey Anisimov, Minah Kim, Breanna Allen, Shentong Fang, Gabriela D'Amico, Tuomas Sipilä, Marja Lohela, Tomas Strandin, Antti Vaheri, Seppo Ylä-Herttuala, Gou Young Koh, Donald M. McDonald, Kari Alitalo, Pipsa Saharinen |
Journal of Clinical Investigation | 2016 |
Angiopoietin-Tie signalling in the cardiovascular and lymphatic systems
L Eklund, J Kangas, P Saharinen |
Clinical Science | 2016 |
Endothelial Mechanosignaling: Does One Sensor Fit All?
C Givens, E Tzima |
Antioxidants & Redox Signaling | 2016 |
Constitutive Association of Tie1 and Tie2 with Endothelial Integrins is Functionally Modulated by Angiopoietin-1 and Fibronectin
AC Dalton, T Shlamkovitch, N Papo, WA Barton, LR Languino |
PloS one | 2016 |
Heterogeneity in vascular smooth muscle cell embryonic origin in relation to adult structure, physiology, and disease: Smooth Muscle Embryonic Origins and Physiology
ER Pfaltzgraff, DM Bader |
Developmental Dynamics | 2015 |
The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells
S Savant, S La Porta, A Budnik, K Busch, J Hu, N Tisch, C Korn, AF Valls, AV Benest, D Terhardt, X Qu, RH Adams, HS Baldwin, C Ruiz de Almodóvar, HR Rodewald, HG Augustin |
Cell Reports | 2015 |
Tie1 is required for lymphatic valve and collecting vessel development
X Qu, B Zhou, HS Baldwin |
Developmental Biology | 2015 |
Phosphorylation of Threonine 794 on Tie1 by Rac1/PAK1 Reveals a Novel Angiogenesis Regulatory Pathway
JL Reinardy, DM Corey, C Golzio, SB Mueller, N Katsanis, CD Kontos, R Ramchandran |
PloS one | 2015 |
The TIE Receptor Family
Saharinen P, Jeltsch M, Santoyo MM, Leppänen VM, Alitalo K |
2015 | |
Tie1 deletion inhibits tumor growth and improves angiopoietin antagonist therapy
Gabriela D'Amico, Emilia Anne Korhonen, Andrey Anisimov, Georgia Zarkada, Tanja Holopainen, René Hägerling, Friedemann Kiefer, Lauri Eklund, Raija Sormunen, Harri Elamaa, Rolf Brekken, Ralf H. Adams, Gou Young Koh, Pipsa Saharinen, Kari Alitalo |
Journal of Clinical Investigation | 2014 |
The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation
KE Milam, SM Parikh |
Tissue Barriers | 2014 |
Shear Stress-Initiated Signaling and Its Regulation of Endothelial Function
J Zhou, YS Li, S Chien |
Arteriosclerosis, thrombosis, and vascular biology | 2014 |
Dkk1 and Msx2–Wnt7b Signaling Reciprocally Regulate the Endothelial–Mesenchymal Transition in Aortic Endothelial Cells
SL Cheng, JS Shao, A Behrmann, K Krchma, DA Towler |
Arteriosclerosis, thrombosis, and vascular biology | 2013 |
Skeletal muscle-specific genetic determinants contribute to the differential strain-dependent effects of hindlimb ischemia in mice
JM McClung, TJ McCord, S Keum, S Johnson, BH Annex, DA Marchuk, CD Kontos |
The American Journal of Pathology | 2012 |
Role of Tie1 in Shear Stress and Atherosclerosis
KV Woo, HS Baldwin |
Trends in Cardiovascular Medicine | 2011 |