Beta3-integrin mediates smooth muscle cell accumulation in neointima after carotid ligation in mice.

Abstract

Pharmacological blockade of beta3-integrins inhibits neointimal lesion formation in nonmouse animal models of arterial injury. In contrast, beta3-integrin-deficient (beta3-/-) mice are not protected from neointimal lesion formation after arterial injury. We investigated this discrepancy in beta3-/- and wild-type (beta3+/+) mice using different models of injury. After disruption of the carotid with a transluminal probe, there was no significant difference in neointimal thickening between beta3-/- and beta3+/+ mice. However, after ligation of the carotid without medial disruption, there was reduced neointimal thickening in beta3-/- mice compared with beta3+/+ mice at intervals up to 3 months. Lesion reduction in beta3-/- mice was associated with fewer intimal smooth muscle cells (SMCs) without a difference in SMC apoptosis or proliferation rate compared with beta3+/+ mice, consistent with reduced SMC migration from the media into the intima of beta3-/- mice. Moreover, combined eccentric medial disruption and ligation of the carotid in beta3-/- mice resulted in neointimal lesion formation only at the site of medial disruption. Transplantation of bone marrow cells harvested from beta3+/+ mice into irradiated beta3-/- mice resulted in reduced neointimal lesion formation after carotid ligation injury, confirming the importance of alpha(v)beta3 and not alpha(IIb)beta3 in the attenuated response. The alpha(v)beta3-integrin mediates intimal SMC accumulation that contributes to neointimal thickening in the setting of arterial ligation.