Published online before print October 31, 2002, doi: 10.1161/01.RES.0000044944.99984.25
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Submitted on June 27, 2001
Revised on October 22, 2002
Accepted on October 23, 2002
Determinants of Notch-3 Receptor Expression and Signaling in Vascular Smooth Muscle Cells. Implications in Cell-Cycle Regulation
Alexandre H. Campos ;
From the Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Ga.
* To whom correspondence should be addressed. E-mail: ggibbons{at}msm.edu.
The Notch family of receptors and ligands plays an important role in cell fate determination, vasculogenesis, and organogenesis. Mutations of the Notch-3 receptor result in an arteriopathy that predisposes to early-onset stroke. However, the functional role of the Notch signaling pathway in adult vascular smooth muscle cells (VSMCs) is poorly characterized. This study documents that the Notch-3 receptor, the ligand Jagged-1, and the downstream transcription factor, HESR-1, are expressed in the normal adult rat carotid artery, and that this expression is modulated after vascular injury. In cultured VSMCs, both angiotensin II and platelet-derived growth factor (PDGF) markedly downregulated Notch-3 and Jagged-1 through ERK-dependent signaling mechanisms and prevented the glycosylation of Jagged-1. The downregulation of Jagged-1 and Notch-3 was associated with a decrease in CBF-1-mediated gene transcription activation and a fall in the mRNA levels of the downstream target transcription factor HESR-1. To test the hypothesis that the Notch pathway was coupled to growth regulation, we generated VSMC lines overexpressing the constitutively active form of Notch-3 (A7r5-N3IC). These cells exhibited a biphasic growth behavior in which the growth rate was retarded during the subconfluent phase and failed to decelerate at postconfluence. The lack of cell-cycle arrest in postconfluent A7r5-N3IC was associated with an attenuated upregulation of the cell-cycle inhibitor p27kip relative to control cells. This study documents the regulation of the Jagged-1 and Notch-3 genes in VSMCs by growth factor stimulation as well as a role for Notch-3 as a determinant of VSMC growth.
Key words: angiotensin II • platelet-derived growth factor • vascular remodeling • neointima • glycosylation
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