Abstract 455: Lats1/2 Expression Reduced By The Pathological Flow Triggers Intraplaque Hemorrhage And Distal Pulmonary Thrombosis By Promoting EC Apoptosis And Proliferation In Concert

Abstract

Atherosclerotic and high-risk plaques are predominantly localized to vessel wall regions with disturbed blood flow (d-flow), leading to the theory that d- and low-flow-driven endothelial cells (EC) dysfunction play a role in this process. It has become clear that high flow (h-flow; high shear stress due to increased flow rate) is also critical to developing high-risk plaques including both rupture and erosion. We aim to determine how the high-risk plaque is formed by pathological flow. The pathological flow (both h- and d-flow) resulted in decreased LATS1/2 expression, but physiological laminar flow did not. Within 14 days after inducing LATS1/2 deletion in tamoxifen-inducible EC-specific LATS1 homo /LATS2 homo knock-out mice (LATS1 homo /LATS2 homo -EKO), all the mice (27/27) had died of severe systemic edema, accompanied by increased EC apoptosis and vascular permeability. We generated EC-specific LATS1 he t /LATS2 homo -EKO mice under hypercholesterolemia (H-chol) with pAAV/D377Y-mPCSK9 injections and a high-fat diet (HFD). After 8weeks of HFD, we detected plaque erosion-like lesions at the h- and d-flow area in the aortic arch and carotids, which revealed strong fibrin/fibrinogen-positive organized thrombus formation without a sizeable necrotic core. Interestingly, we also found a significant increase in distal pulmonary thrombosis and EC proliferation in LATS1 he t /LATS2 homo -EKO mice. H-chol increased the incidents of aortic but not lung lesions. We also performed partial left carotid artery ligation (PLCL) and found that d-flow induced by PLCL developed severe atherosclerosis formation with unique intraplaque hemorrhage in H-chol LATS1 he t /LATS2 homo -EKO mice, which was not observed in wild-type mice. In LATS1 he t /LATS2 homo -EKO mice, we found significant increases in 1) EC proliferation, 2) EC apoptosis with senescent phenotype, 3) tissue factor (TF) expression and 4) inflammation, which are collectively referred to as the “pro-thrombotic phenotype” in vivo . These data suggest that pathological flow-induced LATS1/2 degradation promotes EC apoptosis and proliferation simultaneously. This cycle of EC damage-thrombus formation-re-endothelialization results in rapid thrombus enlargement and distal pulmonary thrombosis.