Integrin αvβ3 as a target in the prevention of neointimal hyperplasia

Although major advances have been made in the prevention and treatment of restenosis following coronary and peripheral interventions, the persistent complications of thrombosis and reintervention remain a mainstay for repeat hospitalizations in this patient population. For many years, a ubiquitous cell surface receptor called αvβ3 integrin was the target of investigators in the prevention of restenosis because its interaction with the extracellular matrix was believed to coordinate the migration of smooth muscle cells (SMCs) from the media to the intima, the seminal event in the formation of intimal occlusive lesion. After the publication of uniformly positive animal studies demonstrating that αvβ3 integrin blockade led to a significant reduction in new intimal (neointimal) lesion formation, early clinical trials supported the association of avoidance of target lesion revascularization and the use of antagonists to the SMC integrin αvβ3 and its related platelet integrin αIIbβ3. However, a series of clinical trials subsequently demonstrated that these antagonists did not necessarily prevent revascularizations by inhibiting intimal hyperplasia per se. Additional animal studies subsequently showed that, indeed, in the setting of pre-existing SMCs in the intimal lesion (ie, atherosclerotic plaque, fatty streaks), inhibiting SMC migration by way of β3 integrin blockade was an ineffective approach in the prevention of intimal hyperplasia and restenosis. However, given the wealth of basic and clinical information on the αvβ3 integrin and its antagonists, we discuss in this article our new approach to this old solution by targeting a new clinical problem of early failure arteriovenous access for hemodialysis. Given the uniqueness of arteriovenous access in that there are essentially no significant atherosclerotic lesions in the artery and vein prior to the anastomosis, the seminal event of the migration of SMCs from the media to the neointima could by targeted once again with β3 integrin antagonists.