Published online before print October 31, 2002, doi: 10.1161/01.RES.0000044944.99984.25
© 2002 American Heart Association, Inc.
Molecular Medicine |
Determinants of Notch-3 Receptor Expression and Signaling in Vascular Smooth Muscle Cells
Implications in Cell-Cycle Regulation
From the Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Ga.
Correspondence to Gary H. Gibbons, Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Dr, SW, Research Wing, Room 245, Atlanta, GA 30310. 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
This article has been cited by other articles:
 |
|
 |
|
  S. Jin, E. M. Hansson, S. Tikka, F. Lanner, C. Sahlgren, F. Farnebo, M. Baumann, H. Kalimo, and U. Lendahl Notch Signaling Regulates Platelet-Derived Growth Factor Receptor-{beta} Expression in Vascular Smooth Muscle Cells Circ. Res., June 20, 2008; 102(12): 1483 - 1491. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Delbosc, M. Glorian, A.-S. Le Port, G. Bereziat, M. Andreani, and I. Limon The Benefit of Docosahexanoic Acid on the Migration of Vascular Smooth Muscle Cells Is Partially Dependent on Notch Regulation of MMP-2/-9 Am. J. Pathol., May 1, 2008; 172(5): 1430 - 1440. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kennard, H. Liu, and B. Lilly Transforming Growth Factor- (TGF- 1) Down-regulates Notch3 in Fibroblasts to Promote Smooth Muscle Gene Expression J. Biol. Chem., January 18, 2008; 283(3): 1324 - 1333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Clement, M. Gueguen, M. Glorian, R. Blaise, M. Andreani, C. Brou, P. Bausero, and I. Limon Notch3 and IL-1beta exert opposing effects on a vascular smooth muscle cell inflammatory pathway in which NF-{kappa}B drives crosstalk J. Cell Sci., October 1, 2007; 120(19): 3352 - 3361. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Gridley Notch signaling in vascular development and physiology Development, August 1, 2007; 134(15): 2709 - 2718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Koibuchi and M. T. Chin CHF1/Hey2 Plays a Pivotal Role in Left Ventricular Maturation Through Suppression of Ectopic Atrial Gene Expression Circ. Res., March 30, 2007; 100(6): 850 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Noseda, Y. Fu, K. Niessen, F. Wong, L. Chang, G. McLean, and A. Karsan Smooth Muscle {alpha}-Actin Is a Direct Target of Notch/CSL Circ. Res., June 23, 2006; 98(12): 1468 - 1470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. G. Leblanc, J. F. Meschia, D. T. Stuss, and V. Hachinski Genetics of Vascular Cognitive Impairment: The Opportunity and the Challenges Stroke, January 1, 2006; 37(1): 248 - 255. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Haritunians, T Chow, R P J De Lange, J T Nichols, D Ghavimi, N Dorrani, D M St Clair, G Weinmaster, and C Schanen Functional analysis of a recurrent missense mutation in Notch3 in CADASIL J. Neurol. Neurosurg. Psychiatry, September 1, 2005; 76(9): 1242 - 1248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Liu and R. M. Harland Inhibition of neurogenesis by SRp38, a neuroD-regulated RNA-binding protein Development, April 1, 2005; 132(7): 1511 - 1523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kanda, K. Hayashi, S. Wakino, K. Homma, K. Yoshioka, K. Hasegawa, N. Sugano, S. Tatematsu, I. Takamatsu, T. Mitsuhashi, et al. Role of Rho-Kinase and p27 in Angiotensin II-Induced Vascular Injury Hypertension, April 1, 2005; 45(4): 724 - 729. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Morrow, C. Sweeney, Y. A. Birney, P. M. Cummins, D. Walls, E. M. Redmond, and P. A. Cahill Cyclic Strain Inhibits Notch Receptor Signaling in Vascular Smooth Muscle Cells In Vitro Circ. Res., March 18, 2005; 96(5): 567 - 575. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Proweller, W. S. Pear, and M. S. Parmacek Notch Signaling Represses Myocardin-induced Smooth Muscle Cell Differentiation J. Biol. Chem., March 11, 2005; 280(10): 8994 - 9004. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sakata, F. Xiang, Z. Chen, Y. Kiriyama, C. N. Kamei, D. I. Simon, and M. T. Chin Transcription Factor CHF1/Hey2 Regulates Neointimal Formation In Vivo and Vascular Smooth Muscle Proliferation and Migration In Vitro Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 2069 - 2074. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Tille and M.S. Pepper Hereditary Vascular Anomalies: New Insights Into Their Pathogenesis Arterioscler. Thromb. Vasc. Biol., September 1, 2004; 24(9): 1578 - 1590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Hussain, S. Singhal, H. S. Markus, and D. R.J. Singer Abnormal Vasoconstrictor Responses to Angiotensin II and Noradrenaline in Isolated Small Arteries From Patients With Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Stroke, April 1, 2004; 35(4): 853 - 858. [Abstract] [Full Text] [PDF]
|
|