Vascular Disease

Elastin Keeps Cells in Their Place

Science's STKE  17 Dec 2002:
Vol. 2002, Issue 163, pp. tw469-TW469
DOI: 10.1126/stke.2002.163.tw469

Karnik et al. have obtained evidence suggesting that the extracellular matrix protein elastin acts as an autocrine regulator of vascular smooth muscle proliferation and migration, a finding that could have implications for the therapy of vascular proliferative diseases. Various vascular proliferative diseases, including atherosclerosis and coronary restenosis, are characterized by dedifferentiation, abnormal proliferation, and migration of vascular smooth muscle cells, a pathophysiological reaction to injury that has largely been interpreted as a response to cytokines released by inflammatory cells. By comparing vascular smooth muscle cells from mice lacking elastin to cells from wild-type sibling controls, Karnik et al. showed that that the extracellular matrix protein elastin, which is secreted by vascular smooth cells, inhibited cell proliferation and promoted the development of actin stress fibers, a marker for a mature contractile phenotype. Elastin influenced cell migration: vascular smooth muscle cells migrated through a filter in response to an elastin concentration gradient but elastin inhibited the cells' migration in response to a platelet-derived growth factor gradient. EDTA, which binds divalent cations thereby inhibiting integrin-mediated interactions, did not inhibit elastin's effects. Rather, pharmacological analysis indicated that elastin activates a guanosine triphosphate (GTP)-binding protein pathway involving a Gi-mediated reduction in cellular cyclic adenosine monophosphate and the stimulation of Rho. In an in vivo porcine model of coronary artery stenosis, insertion of an elastin sheath into arteries following vascular injury reduced the pathophysiological response, suggesting the possibility that elastin's effects on vascular smooth muscle could be exploited in the therapy of vascular proliferative diseases.

S. K. Karnik, B. S. Brooke, A. Bayes-Genis, L. Sorensen, J. D. Wythe, R. S. Schwartz, M. T. Keating, D.Y. Li, A critical role for elastin signaling in vascular morphogenesis and disease. Development 130, 411-423 (2002). [Abstract] [Full Text]