Low blood flow after angioplasty augments mechanisms of restenosis - Inward vessel remodeling, cell migration, and activity of genes regulating migration

The predominant cause of restenosis after angioplasty is now thought to be inward remodeling, but the mechanisms responsible are unknown. Remodeling i n normal vessels is regulated by the endothelium in response to altered she ar stress. Although the endothelium is often damaged by angioplasty, resten osis rates after angioplasty have been correlated with impaired coronary fl ow. Thus, we examined how increases or decreases in blood flow through ball oon catheter-injured rat carotid arteries affect vessel morphometry (4, 10, and 28 days), cell migration (4 days), and levels of promigratory mRNAs (2 and 10 days). After 28 days, the luminal area in vessels with low blood fl ow was significantly less than in those with normal and high blood flow (0. 17 +/-0.01 [low] versus 0.24 +/-0.06 [normal] versus 0.30 +/-0.02 [high] mm (2), P<0.01), predominantly because of accentuated inward remodeling (or re duced area within the external elastic lamina; 0.42<plus/minus>0.02 [low] v ersus 0.54 +/-0.07 [normal] versus 0.53 +/-0.04 [high] mm(2), P<0.05). Low flow also enhanced smooth muscle cell migration 4 days after injury by 90% above normal and high flows (P<0.01). Two days after injury, low flow signi ficantly increased levels of mRNAs encoding promigratory peptides (integrin alpha (v)beta (3), transforming growth factor-beta (1), CD44v6, MDC9, urok inase plasminogen activator receptor, and beta -inducible gene h3); these c hanges persisted 10 days after injury and were localized to the neointima. Low blood flow may promote restenosis after angioplasty because of its adve rse effect on vessel remodeling, and it is associated with the augmented ex pression of multiple genes central to cell migration and restenosis.