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Molecular and Cellular Biology, August 2003, p. 5401-5408, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5401-5408.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Thrombospondin 2 Regulates Cell Proliferation Induced by Rac1 Redox-Dependent Signaling

Neuza Lopes,1 David Gregg,1 Sanjay Vasudevan,1 Hamdy Hassanain,2 Pascal Goldschmidt-Clermont,1* and Hervé Kovacic3*

Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710,1 Heart and Lung Research Institute, Ohio State University, Columbus, Ohio 43210,2 UMR CNRS 6032, Faculté de Pharmacie, Université de la Méditerranée, 13385 Marseille, France3

Received 1 November 2002/ Returned for modification 11 December 2002/ Accepted 14 May 2003

Thrombospondin 2 (TSP2) is a matricellular protein controlling the apoptosis-proliferation balance in endothelial cells. Little is known about its transcriptional regulation compared with that of TSP1. We found that overexpression of a constitutively active mutant of Rac (RacV12) specifically increases TSP2 mRNA levels without affecting TSP1 in human aortic endothelial cells (HAEC). Moreover, TSP2 induction by RacV12 is dependent upon reactive oxygen species (ROS) production, as gp91ds-tat peptide, an inhibitor of NADPH oxidase, and the flavoprotein inhibitor diphenylene iodinium (DPI) block TSP2 synthesis. Furthermore, we found that increasing RacV12 expression results in a biphasic proliferative curve, with proliferation initially increasing as RacV12 expression increases and then returning to levels less than that of control cells at higher expression. This growth inhibition is mediated by TSP2, as either DPI treatment, which blocks TSP2 synthesis, or pan-TSP blocking antibodies restore the proliferative ability of HAEC with high expression. Mechanistically, we show that the effect of TSP2 on cell proliferation is independent of the antiangiogenic TSP2 Hep1 sequence, which is capable of altering actin cytoskeletal reorganization but not proliferation in our experimental conditions. Finally, we show in vivo that Rac-induced TSP2 expression is observed in the aorta of transgenic mice selectively expressing RacV12 in smooth muscle cells. These results identify Rac-induced ROS as a new pathway involved in the regulation of TSP2 expression.

* Corresponding author. Mailing address for Pascal Goldschmidt-Clermont: Division of Cardiology, College of Medicine, Duke University, Durham, NC 27710. Phone: (919) 668-1755. Fax: (919) 668-1861. E-mail: golds017{at}mc.duke.edu. Mailing address for Hervé Kovacic: UMR CNRS 6032, Faculté de Pharmacie, Marseille 13005, France. Phone: (33) 491 835 617. Fax: (33) 491 782024. E-mail: kovacic{at}pharmacie.univ-mrs.fr.

Molecular and Cellular Biology, August 2003, p. 5401-5408, Vol. 23, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.15.5401-5408.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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