Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice

Abstract

Rationale Superficial erosion currently causes up to a third of acute coronary syndromes (ACS), yet we lack understanding of its mechanisms. Thrombi due to superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation. Objective This study tested in vivo the involvement of disturbed flow, and of neutrophils, hyaluronan, and TLR2 ligation in superficial intimal injury, a process implicated in superficial erosion. Methods and Results : In mouse carotid arteries with established intimal lesions tailored to resemble the substrate of human eroded plaques, acute flow perturbation promoted downstream endothelial cell (EC) activation, neutrophil accumulation, EC death and desquamation, and mural thrombosis. Neutrophil loss-of-function limited these findings. TLR2 agonism activated luminal ECs, and deficiency of this innate immune receptor decreased intimal neutrophil adherence in regions of local flow disturbance, reducing EC injury and local thrombosis (p<0.05). Conclusions These results implicate flow disturbance, neutrophils, and TLR2 signaling as mechanisms that contribute to superficial erosion, a cause of ACS of likely growing importance in the statin era.

Mechanisms of erosion of atherosclerotic plaques

“…5,6 Observations on cultured human endothelial cells and on atherosclerotic mice support overexpression of TLR2 in regions of disturbed flow. 7,8 Endothelial cells in human atherosclerotic arteries distal to stenoses, regions that experience disturbed flow, show increased indices of cell death by apoptosis.…”

“…Our recent study tested in mice the involvement of these factors in superficial intimal injury in vivo . 6 We crafted intimal lesions in mouse carotid arteries that resemble the substrate of human eroded plaques by having high extracellular matrix content, but scant macrophages, intimal lesions and lipid. This preparation used electrical injury to the adventitia, followed by 4 weeks of healing to form a neointima and allow re-endothelialization of the intimal surface.…”

Renovascular Hypertension Aggravates Atherosclerosis in Cholesterol-Fed Rabbits

“…First, elevated BP may directly induce endothelial dysfunction or activation [31]. These activated endothelial cells expressed high levels of intercellular adhesion molecule-1 (ICAM-1) and endothelial-leukocyte adhesion molecule-1 (E-selection) which facilitates monocyte migration into the intima [32]. Our current study also showed that macrophage contents in the lesions were significantly increased in HTN rabbits.…”

PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis

“…A large subset of such plaques continues to grow until they cause myocardial ischemia, leading to angina pectoris. Moreover, an emerging paradigm focusing on superficial plaque erosion, departing from the classical thrombotic rupture has been suggested (3–5). Clinical practice relies on detecting ischemia of obstructive lesions to diagnose risk, leaving features like plaque burden and outward remodeling underappreciated (6).…”