Apoptosis, proliferation, and p27 expression during vessel wall healing: Time course study in a mouse model of transluminal femoral artery injury

Objective: The balance between cell death and proliferation in the vessel wall influences neointimal formation, remodeling, and eventual luminal narrowing after arterial injury. In this study, the time course of apoptosis, proliferation, and expression of p27 - a critical regulator of cell-cycle progression - is characterized in a mouse model of transluminal arterial injury associated with substantial neointimal formation. Methods: C57BL/6 mice underwent bilateral femoral artery injury by passage of an angioplasty guidewire. Expression of p27, Ki67 proliferative index, and apoptosis, as well as histomorphometry, were analyzed in cross sections of uninjured arteries and arteries harvested at different time intervals after injury. Results: In the uninjured arteries, no apoptotic cells were detected, and p27 and Ki67 were expressed in less than 5% of medial cells. After injury, apoptosis increased markedly in medial smooth muscle cells from 1 to 24 hours and decreased gradually thereafter. Ki67 proliferative index increased after 1 week, peaked at 2 weeks in both the media and neointima, and decreased thereafter. p27 expression was undetectable from 1 to 48 hours, and increased gradually from 1 to 4 weeks. Well-developed neointima was present at 2 and 4 weeks. Conclusions: In vivo injury to the mouse femoral artery evokes a rapid apoptotic response and downregulation of p27, followed by gradual increase in proliferation. During later phases of arterial repair, p27 expression increases while a shift of proliferation rates toward baseline occurs. Future experiments using this model in genetically modified mice may help identify specific cell-cycle regulatory molecules as therapeutic targets for control of pathologic arterial healing.