Smooth muscle cell interaction with fibrin-A possible mechanism for vessel narrowing during atherosclerosis

Abstract

Atherosclerosis is a disease that causes lumen narrowing in the vasculature. Recent studies suggest that integrin antagonists may inhibit narrowing by preventing cell interaction with the extracellular matrix in the plaque. A number of in vitro assays were developed in order to identify potential integrins important in mediating smooth muscle cell adhesion to, contraction of and migration towards fibrin. Antibodies to alpha5beta1 significantly inhibited smooth muscle cell adhesion to and contraction of fibrin dots while antibodies to alphavbeta3 only had a slight effect. Cell migration on fibrin was modestly affected by these antibodies; however, together both alphavbeta3 and alpha5beta1 antibodies blocked smooth muscle migration on fibrin. A pan-integrin antagonist and disintegrin, Kistrin, also had the same effect suggesting that both integrins may play a role in smooth muscle interaction with fibrin. Because both alphavbeta3 and alpha5beta1 are receptors for fibronectin, the role of fibronectin in smooth muscle cell interaction with fibrin was further characterized. An antibody against fibronectin inhibited smooth muscle cell adhesion and contraction of fibrin clots. Fibronectin was found on both the cell surface and in the sources of fibrinogen.In conclusion, I have demonstrated that the integrin alpha5beta1 and the matrix molecule, fibronectin, play an important role in smooth muscle cell interaction with fibrin. By demonstrating that smooth muscle cells utilize these proteins to adhere, contract and migrate on a fibrin matrix, I suggest that this interaction could cause lumen narrowing during atherosclerosis. Indeed, both fibrin and fibrinogen are found in the plaque in vivo and smooth muscle cells in the lesions do not express high levels of alphavbeta3 but predominately express alpha5beta1 This is especially seen in areas where smooth muscle cells are co-localized with fibrin. Finally, the work presented here on the disintegrin Kistrin suggest that a pharmaceutical reagent that targets several integrins may be an effective drug to inhibit lumen narrowing during atherosclerosis progression.