Photodynamic Therapy for Aortic Aneurysms

Project Summary Abdominal aortic aneurysms (AAA) are a leading cause of death worldwide, and no medical treatment is currently available. It is now accepted that aneurysm growth is related to chronic progressive tissue destruction secondary to vascular inflammation, resulting in the breakdown of extracellular matrix (ECM) proteins. We have shown that a tailored Photodynamic Therapy (PDT) protocol in a mouse model can halt aortic aneurysm growth 21 days after AAA induction. Photodynamic therapy has been shown to enhance cross-linking of collagen, a key component of aortic ECM. This cross-linking substantially increases the strength of ECM. Further, in oncologic studies, PDT appears to selective kill rapidly dividing cells with an affinity for proliferating immune cells. Therefore, we hypothesize that applying PDT to AAA will enhance ECM cross-linking and eradicate proliferating immune cells within the adventitia layer of the vascular wall. Our specific aims are designed to test these hypotheses and determine the mechanism of action behind PDT treatment of AAA. In Aim 1 we will compare the changes to ECM proteins after PDT to what occurs in control mice. We will also evaluate matrix metalloproteases (MMPs) and tissue inhibitors of MMPs (TIMPs), key enzymatic regulators of ECM degradation. In Aim 2 we will investigate the changes in immune cell subpopulations within aortic tissue after PDT. In addition, we will use unbiased analysis to identify changes to gene expression of inflammatory proteins within aortic tissue after delivery of PDT. As our preliminary findings show that PDT can have a powerful effect on AAA growth, analysis of the molecular changes that coincides with this deceleration in growth may lead to a better understanding of the mechanisms that drive AAA progression. In addition, understanding the therapeutic mechanism of PDT may allow PDT to adapted for use in human AAA disease.