This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lopes, N. Articles by Kovacic, H. Search for Related Content PubMed PubMed Citation Articles by Lopes, N. Articles by Kovacic, H.

 Previous Article  |  Next Article 

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

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 (Rac^V12) specifically increases TSP2 mRNA levels without affecting TSP1 in human aortic endothelial cells (HAEC). Moreover, TSP2 induction by Rac^V12 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 Rac^V12 expression results in a biphasic proliferative curve, with proliferation initially increasing as Rac^V12 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 Rac^V12 in smooth muscle cells. These results identify Rac-induced ROS as a new pathway involved in the regulation of TSP2 expression.

This article has been cited by other articles:

• Zhang, A., Liu, X., Cogan, J. G., Fuerst, M. D., Polikandriotis, J. A., Kelm, R. J. Jr., Strauch, A. R. (2005). YB-1 Coordinates Vascular Smooth Muscle {alpha}-Actin Gene Activation by Transforming Growth Factor {beta}1 and Thrombin during Differentiation of Human Pulmonary Myofibroblasts. Mol. Biol. Cell 16: 4931-4940 [Abstract] [Full Text]  
• Li, J.-M., Shah, A. M (2004). Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287: R1014-R1030 [Abstract] [Full Text]