Recombinant soluble P-selectin glycoprotein ligand-1-Ig reduces restenosisthrough inhibition of platelet-neutrophil adhesion after double angioplasty in swine

Background-P-selectin mediates leukocyte recruitment to activated platelets and endothelium through its high-affinity receptor P-selectin glycoprotein ligand-1 (PSGL-1). Platelet and leukocyte activation and binding have been reported after coronary angioplasty and were correlated with restenosis, W e investigated the effect of a recombinant soluble PSGL-1 (rPSGL-Ig) on the adhesion of platelets and neutrophils and the development of restenosis af ter double arterial injury. Methods and Results-Four weeks after angioplasty of both carotid arteries i n pigs, a second angioplasty was performed at the same sites, 15 minutes af ter a single administration of vehicle or rPSGL-1 (1 mg/kg IV). Animals wer e euthanized 1 hour, 4 hours, 1 week, or 4 weeks later. Adhesion of autolog ous Cr-51-platelets and In-111-neutrophils was quantified and histological/ morphometric analyses were performed. Although rPSGL-Ig did not affect adhe rence of these cells 1 hour after injury, it significantly reduced the adhe sion of platelets (50% at 4 hours and 85% at 1 week) and neutrophils (50% a t 4:hours and 78% at 1 week) to deeply injured arteries, At 4 weeks, the re sidual lumen was 63% larger in rPSGL-Ig-treated arteries as compared with c ontrol arteries (6.1+/-0.6 versus 3.8+/-0.1 mm(2); P<0.002). The neointimal area was slightly reduced (0.5 in rPSGL-Ig versus 0.7 mm(2) in control). T he ratio of the external elastic lamina of injured to uninjured reference s egments was >1 in treated arteries and <1 in control arteries. Conclusions-P-selectin antagonism with rPSGL-Ig inhibits early platelet/leu kocyte adhesion on injured arteries and reduces restenosis through a positi ve impact on vascular remodeling. Hence, rPSGL-Ig may have potential in the prevention of restenosis.