The Role of Fibrinolysis in Tissue Engineered Vascular Grafts for Aged Individuals

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SUMMARY As our aging population grows, so does the national need for a readily available and dependable small-diameter conduit for bypass grafting (for coronary and other small arteries) and for hemodialysis access, as current options are limited. While small-diameter tissue engineered vascular grafts (TEVGs) have shown great clinical promise, our current understanding of them has been almost exclusively derived from implantations into young recipients, even though older patients are the demographic most commonly in need of arterial bypass or hemodialysis. Further, these older patients also typically have high levels of the plasma protein plasminogen activator inhibitor- 1 (PAI-1), which could jeopardize the success of a TEVG. Therefore, the goals of this proposal are to understand how our small diameter TEVG performs differently in aged vs young recipients and to identify an intervention that will improve performance in aged individuals. The proposed work has two Specific Aims, each with their own testable hypothesis: Specific Aim 1 – Evaluate how recipient age affects the success of TEVG implantation and levels of circulating PAI-1. We hypothesize that TEVG remodeling and patency are compromised in elderly recipients in comparison to grafts in young or middle-aged recipients, and that elevated PAI-1 levels will be associated with increasing age. The important outcome of this aim will be determining whether middle-aged or elderly recipients are competent for generating a successful TEVG, and if increased plasma PAI-1 is associated with TEVG failure. Specific Aim 2 – Test the effect of pharmacological PAI-1 antagonism on the success of TEVG implantation in aged animals. PAI-1 plays a critical physiological role by preventing premature clot removal after injury, yet chronic elevation of PAI-1 is associated with increased incidence of cardiovascular disease. Metformin, an FDA-approved drug for type 2 diabetes, has been shown to inhibit PAI-1 production. In preliminary work, we show that Klotho, a protein linked to human lifespan extension, can lower age-associated PAI-1 elevation in injured muscle. We hypothesize that antagonism of PAI-1 in aged animals by supplementation with Metformin or Klotho will restore the success (patency rate) of our TEVGs to that of younger animals. Innovation: Despite the disproportionate occurrence of vascular disease in elderly individuals, pre- clinical testing of TEVGs rarely uses aged animal models. The innovation of the proposed work includes the unique combination of an off-the-shelf cell-free tubular scaffold, assessment of PAI-1 levels and TEVG performance in different aged recipients, and evaluation of a pharmacological intervention using the FDA- approved diabetes drug Metformin and longevity-associated protein Klotho to improve age-associated deficient TEVG performance. The carefully-chosen combination of studies proposed here will not only be foundational for tailoring a translatable TEVG for those who are most in need – elderly patients – but may also be paradigm- shifting in how TEVGs and other tissue engineering-based therapies are tested preclinically.