Direct evidence for the importance of p130 in injury response and arterial remodeling following carotid artery ligation.

OBJECTIVE Remodeling of arterial morphology in atherosclerosis, hypertension, and restenosis following angioplasty involves controlled alterations in total vascular circumference which critically modulate sequelae of changes in vessel wall mass. Despite the clinical relevance of this process little is known about the pathophysiology, especially the correlation between smooth muscle cell proliferation and remodeling. METHODS Carotid artery ligation was applied to mice with targeted disruption of the p130 gene (p130 -/-). Mice were allowed to recover for 3 weeks after ligation and then perfusion fixed for histologic and morphometric analysis. RESULTS P130 -/- mice were indistinguishable from control littermates concerning size and weight. As for the aorta, carotid arteries and femoral arteries, no significant differences were found between the groups with regard to vessel size and cellular density of the vessel wall of non-instrumented vessels. In contrast, following carotid artery ligation we found p130 -/- mice (n=8) to develop a significant increase in vessel wall area compared to controls (n=9). Mean values ranged from 3.07 x 10(-2)+/-0.20 x 10(-2)-3.56 x 10(-2)+/-0.62 x 10(-2) mm(2) for p130 -/- mice versus 2.26 x 10(-2)+/-0.13 x 10(-2)-2.57 x 10(-2)+/-0.26 x 10(-2) mm(2) for controls (p=0.02) along the lesion studied. This increase in vessel wall area was primarily due to a sevenfold mean increase in neointima in p130 -/- mice yielding mean values of 0.43+/-0.18 - 1.19+/-0.70 x 10(-2) mm(2). Remarkably, despite vessel wall increase, the lumen area was not statistically different for both groups. CONCLUSIONS The data indicate that the loss of the cell cycle inhibitor p130 leads to an enhanced injury response, implicating a central role of p130 in cell cycle control during response to injury in the vessel wall. The enhanced injury response in the context of p130 -/- preserves the ability to perform perfect remodeling, thus the remodeling capacity is preserved even in the context of this injury model.