Atherosclerotic Lesion Size and Vulnerability Are Determined by Patterns of Fluid Shear Stress

TLDR

Atherosclerotic lesions preferentially develop in arterial regions with low or oscillatory shear stress, yet the effect of these flow patterns on plaque vulnerability has remained unclear. The authors engineered a perivascular shear‑stress modifier to impose localized lowered, increased, or oscillatory shear in mouse carotid arteries and examined the resulting plaque formation and composition. Lesions formed only in regions of lowered or oscillatory shear; lowered‑shear lesions were larger, lipid‑rich, collagen‑poor, had fewer smooth‑muscle cells, greater remodeling, higher inflammatory mediators and MMP activity, and hemorrhages, whereas oscillatory shear produced stable lesions, showing that both shear patterns are essential but generate distinct plaque phenotypes.

Abstract

Background— Atherosclerotic lesions are predominantly observed in curved arteries and near side branches, where low or oscillatory shear stress patterns occur, suggesting a causal connection. However, the effect of shear stress on plaque vulnerability is unknown because the lack of an appropriate in vivo model precludes cause-effect studies. Methods and Results— We developed a perivascular shear stress modifier that induces regions of lowered, increased, and lowered/oscillatory (ie, with vortices) shear stresses in mouse carotid arteries and studied plaque formation and composition. Atherosclerotic lesions developed invariably in the regions with lowered shear stress or vortices, whereas the regions of increased shear stress were protected. Lowered shear stress lesions were larger (intima/media, 1.38±0.68 versus 0.22±0.04); contained fewer smooth muscle cells (1.9±1.6% versus 26.3±9.7%), less collagen (15.3±1.0% versus 22.2±1.0%), and more lipids (15.8±0.9% versus 10.2±0.5%); and showed more outward vascular remodeling (214±19% versus 117±9%) than did oscillatory shear stress lesions. Expression of proatherogenic inflammatory mediators and matrix metalloproteinase activity was higher in the lowered shear stress regions. Spontaneous and angiotensin II–induced intraplaque hemorrhages occurred in the lowered shear stress regions only. Conclusions— Lowered shear stress and oscillatory shear stress are both essential conditions in plaque formation. Lowered shear stress induces larger lesions with a vulnerable plaque phenotype, whereas vortices with oscillatory shear stress induce stable lesions.