Inhibition of the intimal hyperplasia in an arterial autograft model by blockade of the N-terminal of the integrin beta 3 subunit by monoclonal antibody P37

Myointima formation or intimal hyperplasia is a major undesirable problem at the anastomotic ends of narrow bore arterial autografts and in other arterial wall injuries, which often leads to late restenosis and thrombosis and whose pathogenesis is still not understood. Platelets are suspected to intervene at some stages of its development, together with endothelial and muscle cells, the extracellular matrix and, most probably, adhesion receptors. To ascertain whether and at what stage beta 3 integrins are involved, a rat arterial autograft model was used, together with monoclonal antibody P37, which is directed to the sequence 101-109 of the beta 3 subunit of the human platelet fibrinogen receptor (integrin alpha IIb beta 3) and inhibits platelet aggregation in vitro and acute thrombosis in vivo. Three groups of animals were used: group I underwent an arterial autograft of a 5-mm segment of the right common iliac artery; group II received, intravenously, a single dose (0.8 mg/kg) of P37 at 15 min before the graft implantation; and group III was treated as group II but a similar dose of antibody was additionally given on day 14 after the operation. Animals in each group were sacrificed on days 7, 14, 21, 30 and 50 after the operation, and the grafts were removed for light and electron microscopy observation and further time-dependent morphometric analysis. By day 14, group I autografts already showed intimal hyperplasia and secretory smooth muscle cells, while group II and II autografts presented only some degenerative changes in the medial layer, with no signs of hyperplasia. Intimal hyperplasia was observed on day 21 in group II and on day 30 in group III, although less pronounced than in the corresponding controls. However, by day 50, the three groups had the same thickness of myointima. The immunohistochemical determination of metalloproteases suggests no role for these enzymes in the immunoinhibition of myointima formation, We conclude that P37 inhibits the onset of the intimal hyperplasia in the arterial autografts and that this onset in treated animals seems to be related to the decay of the circulating antibody. Further work is required to decide whether a higher or longer presence of circulating P37 can definitively prevent the development of intimal hyperplasia, as well as to ascertain which cells and which beta 3 integrin receptors intervene.