Abstract 139: Precision Nanomedicine Targeting Novel Endothelial Mechano-sensing Mechanisms To Treat Vascular Diseases

Abstract

Endothelial mechano-transduction mechanisms are instrumental to vascular health and disease but targeting disease-causing mechano-sensing pathways remains extremely challenging. Atherosclerosis preferentially develops at arterial curvatures and bifurcations where disturbed blood flow activates endothelium, leading to peripheral artery disease, carotid artery disease and ischemic stroke. Nevertheless; current atherosclerosis therapies mainly target systematic risk factors but not the vasculature per se . This underscores the significance and unique opportunity to identify and target novel mechanosensitive mechanisms in activated endothelium subjected to disturbed flow. Our objectives are to (1) delineate novel endothelial mechano-sensing mechanisms and (2) devise innovative precision nanomedicine approaches targeting these disease-causing mechano-sensitive pathways. Using multiple new transgenic mouse lines, our studies demonstrated that disturbed flow (DF) significantly increases the endothelial expression of TXNDC5 (thioredoxin domain containing 5) and microRNA-92a (miR-92a), two atherogenic molecules driving atherogenesis. Mechanistically, DF-induced TXNDC5 increases proteasome-mediated degradation of heat shock factor 1 and consequently promotes eNOS/NOS3 protein degradation. Meanwhile, DF induces endothelial miR-92a to suppress key anti-inflammatory molecules such as KLF2, KLF4, and PLPP3. We successfully formulated nanoparticles to deliver TXNDC5-targeting CRISPR/Cas9 plasmids driven by an endothelium-specific promoter (CDH5), which effectively deleted endothelial TXNDC5 expression and reduced atherosclerosis in Apoe -/- mice. Moreover, VCAM1-tageting polyelectrolyte complex micelles were engineered to selectively deliver miR-92a inhibitors to inflamed endothelium, which markedly decreased arterial stenosis and atherosclerosis in Apoe -/- mice. These results elucidate novel endothelial mechano-sensing mechanisms and provide a proof of concept of innovative targeted nanomedicine approaches, addressing an unmet medical need in vascular therapies.