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A critical role for elastin signaling in vascular morphogenesis and disease.
- Source :
-
Development (Cambridge, England) [Development] 2003 Jan; Vol. 130 (2), pp. 411-23. - Publication Year :
- 2003
-
Abstract
- Vascular proliferative diseases such as atherosclerosis and coronary restenosis are leading causes of morbidity and mortality in developed nations. Common features associated with these heterogeneous disorders involve phenotypic modulation and subsequent abnormal proliferation and migration of vascular smooth muscle cells into the arterial lumen, leading to neointimal formation and vascular stenosis. This fibrocellular response has largely been attributed to the release of multiple cytokines and growth factors by inflammatory cells. Previously, we demonstrated that the disruption of the elastin matrix leads to defective arterial morphogenesis. Here, we propose that elastin is a potent autocrine regulator of vascular smooth muscle cell activity and that this regulation is important for preventing fibrocellular pathology. Using vascular smooth muscle cells from mice lacking elastin (Eln(-/-)), we show that elastin induces actin stress fiber organization, inhibits proliferation, regulates migration and signals via a non-integrin, heterotrimeric G-protein-coupled pathway. In a porcine coronary model of restenosis, the therapeutic delivery of exogenous elastin to injured vessels in vivo significantly reduces neointimal formation. These findings indicate that elastin stabilizes the arterial structure by inducing a quiescent contractile state in vascular smooth muscle cells. Together, this work demonstrates that signaling pathways crucial for arterial morphogenesis can play an important role in the pathogenesis and treatment of vascular disease.
- Subjects :
- Actins metabolism
Animals
Autocrine Communication physiology
Blood Vessels anatomy & histology
Cell Line
Cell Movement physiology
Cyclic AMP metabolism
Elastin genetics
GTP-Binding Proteins metabolism
Humans
Mice
Morphogenesis physiology
Muscle, Smooth, Vascular metabolism
Phenotype
Regression Analysis
Stents
Swine
Tubulin metabolism
Vinculin metabolism
rhoA GTP-Binding Protein metabolism
Blood Vessels physiology
Elastin metabolism
Signal Transduction physiology
Vascular Diseases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0950-1991
- Volume :
- 130
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Development (Cambridge, England)
- Publication Type :
- Academic Journal
- Accession number :
- 12466207
- Full Text :
- https://doi.org/10.1242/dev.00223