Metabolic Reprogramming in Experimental Deep Vein Thrombosis and Resolution - Project summary Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and its major short-term complication, pulmonary embolism (PE), represents a significant health issue in the US and worldwide. The mainstay of current DVT treatment is oral anticoagulant therapy. It decreases the risk of DVT reoccurrence but, unfortunately, does not mitigate inflammation or facilitate venous thrombus (VT) resolution, which correlates with postthrombotic syndrome (PTS) in humans. Even pharmaco-mechanical thrombectomy allows the removal of only limited amounts of thrombus and has minimal efficacy in preventing PTS. Therefore, significant therapeutic gaps exist in providing safer and more effective treatments for DVT and PTS. Given the thromboinflammatory nature of DVT, the major problem is that resolving or residual venous thrombus, even after partial removal via systemic or catheter-directed thrombolysis or stenting, confers local inflammation, leading to persistent fibrotic venous wall injury resulting in PTS. We propose to address this problem by testing the innovative concept that manipulating metabolic reprogramming by targeting dimeric pyruvate kinase M2 (PKM2) in platelets and neutrophils will inhibit acute venous thrombus formation and, at later stages, targeting PKM2 in macrophages will enhance efferocytosis, thereby limiting fibrotic venous wall injury and accelerating VT resolution. The concept builds upon our exciting findings that limiting PKM2 dimerization inhibits platelet activation, reprograms pro-inflammatory into anti-inflammatory macrophages, and enhances the macrophages’ efferocytotic activity—the ability to clear apoptotic cells that are known to exacerbate inflammation—and inhibits collagen synthesis in vein fibroblasts. Using human samples and cell-specific mutant mice, we propose further defining whether metabolic reprogramming by targeting dimeric PKM2 limits chronic inflammation and accelerates VT resolution. In Aim 1, we will define the regulatory role of PKM2 in acute DVT progression. In Aim 2, we will determine whether targeting PKM2 at later stages will limit local inflammation, accelerate VT resolution, and prevent PTS. A strength of the proposal is that we propose to test novel strategies to improve vascular integrity and motor function in the DVT-affected limb using the femoral vein thrombosis model in mice and rats. Our team has extensive collaborative expertise, which will increase the feasibility and the likelihood of success. The overall impact of the proposed research is high because the knowledge gained from this proposal will significantly move the field of DVT by defining novel mechanisms contributing to common pathways from acute to chronic inflammation and leading to fibrotic damage of the venous wall.
