Kinetics of smooth muscle cell proliferation and intimal thickening in a pig carotid model of balloon injury.

Restenosis as a result of neointimal smooth muscle cell accumulation is an important limitation to the effectiveness of balloon angioplasty as a treatment for end-stage atherosclerosis. Quantitative animal models allow the definition of pathophysiological mechanisms and the evaluation of new therapeutic strategies. In this study we quantified the time course of neointima formation by morphometry, and smooth muscle cell (SMC) proliferation by immunocytochemistry for proliferating cell nuclear antigen (PCNA), in the pig carotid artery 0-28 days following balloon injury. This led to two distinct kinds of injury observed also in clinical studies, namely medial dilatation or deep medial tearing with rupture of the internal elastic lamina. Dilatation injury alone led to medial enlargement and neointima formation by 7 days, which did not increase further up to 28 days. Medial enlargement was similar following rupture of the internal elastic lamina; however the sum of neointima formation plus the area of medial repair ('neomedia') increased progressively up to 21 days after balloon injury. Balloon injury increased the PCNA index of smooth muscle cells in the media underlying an intact internal elastic lamina maximally after 3 days. The PCNA index in the neointima and especially in the neomedia was greater and maximal after 7 days. Endothelial regrowth occurred by 21 days in the presence or absence of medial tears. Our results establish a quantitative pig model of balloon injury which will allow the assessment of new therapeutic strategies directed at two clinically relevant types of injury. Medial tearing is associated with an enhanced and localized proliferative response and may therefore be especially important in human restenosis.