Published online before print July 3, 2003, doi: 10.1161/01.ATV.0000084639.16462.7A
© 2003 American Heart Association, Inc.
Vascular Biology |
TR3 Orphan Receptor Is Expressed in Vascular Endothelial Cells and Mediates Cell Cycle Arrest
From the Departments of Biochemistry (E.K.A., M.v.B., H.P., C.J.M.d.V.), Experimental Immunology (E.E.), and Radiotherapy (C.v.B.), Academic Medical Center, University of Amsterdam, Amsterdam, and the Gaubius Laboratory TNO-PG (J.M.G., P.H.A.Q.), Leiden, the Netherlands.
Correspondence to Carlie J.M. de Vries, PhD, Department of Biochemistry, Academic Medical Center, K1[hyphen]163, Meibergdreef 15 1105 AZ Amsterdam, The Netherlands. E-mail: c.j.devries{at}amc.uva.nl
Objective— Endothelial cells play a pivotal role in vascular homeostasis. In this study, we investigated the function of the nerve growth factor–induced protein-B (NGFI-B) subfamily of nuclear receptors comprising the TR3 orphan receptor (TR3), mitogen-induced nuclear orphan receptor (MINOR), and nuclear orphan receptor of T cells (NOT) in endothelial cells.
Methods and Results— The mRNA expression of TR3, MINOR, and NOT in atherosclerotic lesions was assessed in human vascular specimens. Each of these factors is expressed in smooth muscle cells, as described before, and in subsets of endothelial cells, implicating that they might affect endothelial cell function. Adenoviral overexpression of TR3 in cultured endothelial cells resulted in decreased [3H]thymidine incorporation, whereas a dominant-negative TR3 variant that inhibits the activity of endogenous TR3-like factors enhanced DNA synthesis. TR3 interfered with progression of the cell cycle by upregulating p27Kip1 and downregulating cyclin A, whereas expression levels of a number of other cell cycle–associated proteins remained unchanged.
Conclusions— These findings demonstrate that TR3 is a modulator of endothelial cell proliferation and arrests endothelial cells in the G1 phase of the cell cycle by influencing cell cycle protein levels. We hypothesize involvement of TR3 in the maintenance of integrity of the vascular endothelium.
Key Words: endothelial cells • TR3 orphan receptor • cell cycle • vascular biology
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