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Molecular and Cellular Biology, July 2004, p. 6151-6161, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6151-6161.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Regulation of Collagen Type I in Vascular Smooth Muscle Cells by Competition between Nkx2.5 and {delta}EF1/ZEB1

Markella Ponticos,1 Terrence Partridge,2 Carol M. Black,1 David J. Abraham,1 and George Bou-Gharios3*

Centre for Rheumatology, Department of Medicine, University College of London, Hampstead, London NW3 2PF,1 Department of Muscle Biology, MRC-Clinical Science Centre,2 Renal Medicine, Department of Medicine, Imperial College London, London W12 ONN, United Kingdom3

Received 15 December 2003/ Returned for modification 28 January 2004/ Accepted 14 April 2004

A major component of the vessel wall of large arteries and veins is the extracellular matrix (ECM), which consists of collagens, elastin, and proteoglycans. Collagen type I is one of the most abundant of the ECM proteins. We have previously shown that the pro-collagen type I alpha 2 gene contains an enhancer which confers tissue-specific expression in the majority of collagen-producing cells, including blood vessels. In this paper, we delineate a specific vascular smooth muscle cell (vSMC) element: a 100-bp sequence around –16.6 kb upstream of the transcription start site that regulates collagen expression exclusively in vSMCs. Furthermore, we show that the expression is activated through the binding of the homeodomain protein Nkx2.5, which is further potentiated in the presence of GATA6. In contrast, this element was repressed by the binding of the zinc-finger protein {delta}EF1/ZEB1. We propose a model of regulation where the activating transcription factor Nkx2.5 and the repressor {delta}EF1/ZEB1 compete for an overlapping DNA binding site. This element is important in understanding the molecular mechanisms of vessel remodeling and is a potential target for intervention in vascular diseases where there is excessive deposition of collagen in the vessel wall.

* Corresponding author. Mailing address: Department of Renal Medicine, Imperial College London, Hammersmith Campus, Du Cane Rd., London W12 0NN, United Kingdom. Phone: 44 (0)208 3832306. Fax: 44 (0)208 3832062. E-mail: g.gharios{at}imperial.ac.uk.

Molecular and Cellular Biology, July 2004, p. 6151-6161, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6151-6161.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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