β 3 Integrins Are Upregulated After Vascular Injury and Modulate Thrombospondin- and Thrombin-Induced Proliferation of Cultured Smooth Muscle Cells

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Abstract
Background —Treatment with an antibody that binds β 3 integrins (abciximab; c7E3 Fab) at the time of coronary angioplasty decreases the need for repeat revascularization. Two potential mechanisms have been proposed to explain this effect: (1) inhibition of platelet aggregation or (2) interruption of ligand binding to β 3 integrins on the smooth muscle cell (SMC) surface. We examined the latter hypothesis by determining (1) if β 3 integrin expression is upregulated after vascular injury in the baboon, (2) if 7E3 binds β 3 integrins on cultured SMC, and (3) if β 3 integrin activation plays a role in proliferation of cultured SMC. Methods and Results —Results demonstrated that immunostaining for β 3 integrins was present in the neointima 1 week after balloon withdrawal injury of baboon brachial arteries and that β 3 integrin expression colocalized with α-actin–positive cells. In contrast, staining for β 3 integrins was undetectable in contralateral uninjured brachial arteries. 7E3 bound to cultured human aortic SMC with an affinity ( K D =3.3 nmol/L) similar to 7E3 binding to endothelial cells or platelets. Cotreatment with 7E3 partially inhibited thrombospondin-induced or α-thrombin–induced proliferation but not PDGF-induced or serum-induced proliferation. Conclusions —In summary, these studies demonstrate that vascular cell β 3 integrin expression is increased after injury, that 7E3 binds to cultured SMC with high affinity, and that β 3 activation is important for thrombospondin-induced or α-thrombin–induced proliferation. These results support the hypothesis that β 3 integrins play a role in SMC growth responses after balloon injury.

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