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doi: 10.1242/10.1242/dev.00223
DEVELOPMENT AND DISEASE |
1 Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake
City, UT, USA
2 Department of Medicine and Oncological Science, University of Utah, Salt Lake
City, UT, USA
3 Hospital Sant Pau, Barcelona, Spain
4 Minnesota Cardiovascular Research Institute, Minneapolis, MN, USA
5 Howard Hughes Medical Institute, Department of Cell Biology, Harvard Medical
School, Department of Cardiology, Children's Hospital, Boston, MA, USA
Author for correspondence (e-mail:
dean.li{at}hmbg.utah.edu)
Accepted 19 October 2002
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.
Key words: Elastin matrix, Vascular smooth muscle, Morphogenesis, G-protein signaling, Vascular proliferative diseases
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