Activation of Smooth Muscle Cell Outgrowth From BB/Wor Rat Aortas

Abstract

An essential event in atherogenesis is the migration and proliferation of vascular smooth muscle cells (VSMCs), which contributes to the fibrocellular component of the atherosclerotic intimai thickening. We have been modeling this process by studying the outgrowth of VSMC from aortic expiants onto tissue-culture plastic substrate. Our hypothesis is that certain risk factors for atherosclerosis favor increases in subpopulations of cells with enhanced responsiveness to a variety of migratory and proliferative stimuli, in vivo and in vitro. As a known risk factor for atherosclerosis, diabetes might be reasonably postulated to induce such cell populations with altered susceptibility to additional noxious stimuli. We have tested this hypothesis with aortic expiants from rats of the spontaneous autoimmune diabetic BB/Wor group, including diabetes-resistant, diabetes-prone, and treated acutely (<2 wk after onset of hyperglycemie) and chronically (>2 wk) diabetic strains. As a group, the VSMCs from BB/Wor animals showed enhanced outgrowth in 0.1% serum (23–48%) compared with VSMCs from ordinary Wistar rats (<10%). Within the BB/Wor group, however, the rank order of enhanced outgrowth was diabetes-resistant > chronically diabetic > acutely diabetic subjects. When the outgrowth assay was performed in the presence of supplemental insulin (10 mU/ml), outgrowth was increased, especially for the diabetes-prone animals, giving a new rank order of diabetes-prone > acutely diabetic > diabetes-resistant > chronically diabetic subjects. These data suggest a genetic predilection in the entire BB/Wor rat group for increased VSMC responsiveness to migratory and proliferative stimuli, a sensitivity of these VSMCs to insulin, and the dissociation of this vascular cell effect from other manifestations of diabetes, e.g., hyperglycemia.