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 CD 31 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 µm, 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.

After balloon angioplasty, retarded endothelial cell recoverage of the injured segment may lead to enhanced intimal hyperplasia. We tested the hypothesis that long lesions result in more intimal hyperplasia than short lesions due to a prolonged time to complete endothelial cell recoverage. A 2-french Fogarty balloon was used to create 2.5- and 5-cm-long lesions in the rabbit carotid artery. After termination, the injured arteries (n = 9 for all groups) were serially processed for histochemistry. Endothelial cell coverage was assessed with an antibody to CD31 and cell proliferation with a monoclonal antibody to Ki-67 nuclear antigen. The intimal hyperplasia cross-sectional area was measured morphometrically. All data are mean +/- SEM. At 21 days, endothelial cell recoverage was almost complete in the 2.5-cm lesions. In the 5-cm lesions, endothelial cell recoverage was 66 +/- 6% in the middle segments (p = 0.04, 2.5 vs. 5 cm) and 100% at the cranial and caudal ends of the lesion. At 42 days, endothelial cell coverage had increased to 81 +/- 7% in the middle segments of the 5-cm lesions. The intimal hyperplasia area was similar in the 2.5- and the 5-cm lesions both at 21 days (0.19 +/- 0.02 and 0.20 +/- 0.01 mm2, respectively) and 42 days (0.27 +/- 0.02 and 0.26 +/- 0.03 mm2, respectively). The increase in intimal hyperplasia from 21 to 42 days was significant for both lesion lengths (p = 0.004). At 21 days, intimal proliferation was similar for the 2.5- and 5-cm lesions. After 42 days postinjury, intimal proliferation had decreased (p < 0.001) equally for both lesion lengths. Earlier recoverage by endothelium in the 2.5-cm lesions did not inhibit intimal hyperplasia compared to the 5-cm lesions which were still incompletely reendothelialized. We conclude that in the rabbit, rapid endothelial cell recoverage of Fogarty balloon-injured arteries may not limit intimal hyperplasia in the center of the lesion. It is conceivable that the inability of regenerated endothelium to inhibit intimal hyperplasia is due to its initially dedifferentiated and possibly dysfunctional phenotype.

Despite comparable endothelial cell abrasion and medial necrosis, Fogarty balloon injury elicited significantly augmented intimal hyperplasia compared with PTCA balloon dilation.

Lipoic acid (LA) exerts its therapeutic value in pathologies in which free radicals are involved. Therefore, we study the anti-oxidant mechanisms of LA.In the protection against lipid peroxidation (LPO), the direct scavenging of free radicals by LA is of minor importance. We determined its indirect anti-oxidant capacity. It was found that in the protection against LPO, dihydrolipoic acid (DHLA) potentiates the protection provided by GSH. It keeps GSH in the reduced, active form. Of the DHLA, consumed during the regeneration proces, only the R-enuntiomer could be enzymatically recycled.During oxidative stress vitamin C is converted into a semi-dehydroascorbate radical and subsequently into dehydroascorbate. DHLA and GSH both regenerate vitamin C. Our experiments show that DHLA regenerates vitamin C much faster.We conclude that the anti-oxidam effect of lipoic acid in the protection against LPO is due to a cooperation with the anti-oxidants GSH and vitamin C. Pharmacy World & &ience ~o,omo t6 Nr, ,9~ J5 1. L.M. de Lannoy et al. Br.