Repeated balloon injury of rat aorta. A model of neointima with attenuated inhibition by heparin.

Abstract

Repeated arterial injury, because it challenges already activated cells, may elicit a reaction that differs from that provoked by a single injury. We compared the response of rat aorta to single and double balloon injury and tested the inhibitory effect of heparin in both situations. For repeated injury, the first and second lesions were induced 3 weeks apart. Two weeks after repeated injury, the neointima that existed from the first lesion had expanded, with significant increases in intima-media wet weight and its DNA and elastin content and in the intima-to-media (I/M) thickness ratio. Two days after repeated injury, the expression of proliferating cell nuclear antigen (PCNA) was enhanced in both the media and the intima, indicating that cells from both layers are involved in the aortic response to a second lesion. As established previously, treatment with heparin (continuous intravenous administration, 50 IU/kg.h-1) almost totally suppressed the response to single injury. However, heparin only attenuated the response to repeated injury, with a partial decrease in intima-media wet weight and its DNA and elastin content and in I/M thickness ratio. PCNA labeling showed that heparin inhibited the proliferative activity in medial cells much more strongly than in intimal cells. In conclusion, repeated aortic injury elicits a reaction of both the media and preexisting neointima. In this mixed response, neointimal smooth muscle cells are less sensitive than medial cells to inhibition by heparin, which results in a weakened effect of the drug on the fibromuscular reaction.