APOPTOSIS AND CELL-PROLIFERATION AFTER PORCINE CORONARY ANGIOPLASTY

Background-Angioplasty initiates a number of responses in the vessel w all including cellular migration, proliferation, and matrix accumulati on, all of which contribute to neointima formation and restenosis. Cel lular homeostasis within a tissue depends on the balance between cell proliferation and apoptosis. Methods and Results-Profiles of apoptosis and proliferation were therefore examined in a porcine PTCA injury mo del over a 28-day period. Forty-two arteries from 21 pigs, harvested a t the site of maximal injury at 1, 6, and 18 hours, and 3, 7, 14, and 28 days after PTCA, were examined (n=3 animals per time point). Uninju red arteries were used as controls. Apoptosis was demonstrated by the terminal uridine nick-end labeling (TUNEL) method, transmission electr on microscopy (TEM), and DNA fragmentation. Cells traversing the cell cycle were identified by immunostaining for proliferating cell nuclear antigen (PCNA). Apoptosis was not detected in control vessels at all time points nor at 28 days after PTCA, Apoptotic cells were identified at all early time points with a peak at 6 hours (5.1+/-0.26%; compare d to uninjured artery, P<0.001) and confirmed by characteristic DNA la dders and TEM findings. Regional analysis showed apoptosis within the media, adventitia, and neointima peaked at 18 hours, 6 hours, and 7 da ys after PTCA, respectively. In comparison, PCNA staining peaked at 3 days after PTCA (7.16+/-0.29%; compared to 1.78 +/- 0.08% PCNA-positiv e cells in the uninjured artery, P<0.001). Profiles of apoptosis and c ell proliferation after PTCA were discordant in all layers of the arte ry except the neointima. These profiles also differed between traumati zed and nontraumatized regions of the arterial wall. Immunostaining wi th cell-type specific markers and TEM analysis revealed that apoptotic cells included vascular smooth muscle cells (VSMCs), inflammatory cel ls, and adventitial fibroblasts. Conclusions-These results suggest tha t the profile of apoptosis and proliferation after PTCA is regional an d cell specific, and attempts to modulate either of these events for t herapeutic benefit requires recognition of these differences.