| Description |
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 abnormal proliferation and migration of vascular smooth muscle cells into the arterial lumen, leading to neointimal formation and vascular stenosis. Unlike other cell types, vascular smooth muscle cells (VSMCs) possess the unique ability to modulate their phenotype based upon extracellular cues. During this modulation, VSMCs undergo a transformation from an immature, proliferative state, to a mature, quiescent one. This modulation occurs during arterial development and forms the basis of obstructive vascular disease. The ability to regulate this process has potential therapeutic implications. Yet, the external stimuli, that govern this process are unknown. Our hypothesis was that the extracellular matrix protein, elastin, regulated VSMC phenotype. This hypothesis was based on studies of Eln -/- mice. Mice lacking the elastin protein die at postnatal day 3.5 from an overproliferation and invasion of the VSMCs lining the neointimal layer of elastic arteries. This lead us to propose that elastin controlled the modulation of VSMCs from an immature to a mature state during arterial development. The disruption of this interaction could thus lead to arterial disease. Here, we demonstrate that elastin functions in an autocrine manner, providing a critical cue for VSMCs during development. We argue that elastin communicates with the VSMC interior, through nonintegrin, nonreceptor tyrosine kinase, pertussis toxin-sensitive G protein coupled receptors. The distal portion of this pathway involves lowered cAMP levels, GiRK activation, and RhoA activation. This works leads us to proposing rudimentary elastin signal transduction pathway and gives us a system to identify an elastin receptor. |
