Platelets in vascular injury repair

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PROJECT SUMMARY/ABSTRACT Percutaneous arterial interventions and arterial bypass surgeries are complicated by the problem of intimal hyperplasia (restenosis). Diabetic patients are more likely to experience restenosis, even after drug-eluting stents. With ever increasing numbers of intravascular (e.g. angioplasty and insertion of devices) and surgical procedures (e.g. bypass) for highly prevalent cardiovascular diseases, optimal resolution of repair is essential. The process of arterial repair after injury is complex. Initiation of repair after injury is well studied with thrombosis followed by inflammation, cellular proliferation and remodeling. Resolution of the repair process is poorly understood, particularly, what constitutes the “brake” to prevent excessive repair? Platelets provide a first and crucial line of defense against vascular injury, initially maintaining hemostasis. Upon activation, platelets also release bioactive mediators such as PDGF and thromboxane, promoting VSMC dedifferentiation from a quiescent contractile phenotype to a highly synthetic and proliferating cell type, promoting injury repair. Excessive repair, such as observed with intimal hyperplasia in diabetes mellitus (DM) after surgical or vascular interventions, can result from enhanced VSMC dedifferentiation and proliferation. We will address the hypothesis that horizontal transfer of platelet-derived miRNAs into VSMCs provide a novel mechanism for regulating VSMC phenotypic switching, preventing excessive repair and intimal hyperplasia. We are in a unique position to address our hypothesis with recognized surgical expertise in vascular surgical interventions and VSMC biology (Alan Dardik MD and Kathleen Martin PhD), platelet expertise (John Hwa MD PhD, Wai Ho Tang PhD), and diabetes mellitus (Silvio Inzucchi MD, Raimund Herzog MD). In the short term we will have presented a novel mechanism for platelet-VSMC interaction and arterial injury repair. In the long term, these mechanistic insights may provide new therapeutic targets in promoting arterial injury repair.