Endothelial cell recoverage and intimal hyperplasia after endothelium removal with or without smooth muscle cell necrosis in the rabbit carotid artery.

Interventional-injury-induced intimal hyperplasia involves smooth muscle cell proliferation that may be limited by endothelial cell coverage. We hypothesized that endothelial cell coverage modulates intimal hyperplasia. Therefore rabbit carotid arteries were injured with (2-french Fogarty balloon) and without media necrosis (Prolene loop). After termination at 3, 7, 21, or 42 days, endothelial cell coverage was assessed with an antibody to CD31 and cross-sectional intimal hyperplasia area was measured morphometrically. At 21 and 42 days, maximal intimal hyperplasia thickness was measured at a site where endothelium was present and where endothelium was absent. Proliferating cells were identified with an antibody to the nuclear antigen Ki-67. From 3 to 42 days, endothelial cell coverage progressed from the caudal and cranial ends of the lesion towards the center and was slower in balloon- versus loop-injured arteries (p<0.001, Anova). At 21 and 42 days, intimal hyperplasia area was larger after balloon than after loop injury (21 days: 0.20 +/- 0.01 vs. 0.09 +/- 0.04 mm2, p<0.05; 42 days: 0.26 +/- 0.03 vs. 0.08 +/- 0.02 mm2, p<0.01). At 21 days, the intimal hyperplasia was maximal at the center of the lesion and diminished towards the edges in both balloon- and loop-injured arteries. Surprisingly, at 21 and 42 days, maximal intimal hyperplasia thickness was larger in CD31-positive compared to CD31-negative regions (104 +/- 8 vs. 72 +/- 12 micron, p<0.01, paired t test). At 3 and 7 days, more medial proliferation was found after balloon than after loop injury (3 days: 46.2 +/- 8.8 vs. 0.2 +/- 0.1%, p<0.01; 7 days: 18.5 +/- 6.4 vs. 1.0 +/- 0.4%, p<0.01). In the same period, abundant adventitial proliferation was found after balloon injury that was entirely absent after loop injury. We conclude, first, that endothelial cell recoverage proceeded at a lower rate over damaged than over normal media. This retarded endothelial cell recoverage may contribute to enhanced intimal hyperplasia. Second, at a late stage of vascular healing, when intimal hyperplasia had already been formed, reendothelialization seems to have been enhanced over areas with thick intimal hyperplasia. Third, dilation-induced medial damage was accompanied with massive adventitial cell proliferation.