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Shear Stress And Monocyte Recruitment In Vein Graft Remodeling: The Interplay Of Physical And Biologic Adaptations

Peng Yu^1,2, Scott A Berceli^1,2, Ming Tao^1,2, C Keith Ozaki^1,2, Zhihua Jiang^1,2 ∙
¹University of Florida, Gainesville, FL; ²Malcom Randall VAMC, Gainesville, FL

OBJECTIVE: Our previous work demonstrated that low wall shear accentuates intimal hyperplasia (IH) within vein grafts (VG). Central to IH development is the leukocyte, and we propose a critical link between the biologic and physical microenvironments in early VG remodeling. Specifically, we hypothesize that the CCR2/MCP-1 pathway is pivotal to leukocyte recruitment, but only in combination with reduced shear forces does this induce monocyte entry into the VG wall and drive the accelerated hyperplastic response.
METHODS: Bilateral rabbit carotid VG was coupled with unilateral partial distal ligation to create a 7-fold flow differential between sides. At implantation, leukocytes were fluorescently labeled to assay leukocyte density within high flow/low flow VG (n=5) at Day 1. Separate VG (n=25) were assayed at 1, 3, 7, 14, 28 days for MCP-1 and CCR-2 mRNA expression. CCR2-/- (n=20) and C57BL/6J control (n=20) mice underwent VG from isogenic donors into the carotid artery, with 12 and 13 of these mice, respectively, undergoing partial carotid branch ligation to create a 75% reduction in wall shear. VG were harvested for morphology at Day 28.
RESULTS: Labeling experiments revealed a 2-fold increase in leukocyte density within VG exposed to low shear (Fig 1), yet no differential in MCP-1 or CCR2 induction between low and high shear VG (Fig 2). Low shear CCR-2 -/- VG demonstrated significantly less IH than low shear controls, yet CCR2 -/- VG IH was not different from controls in the high shear setting (Fig 3).
CONCLUSIONS: Leukocyte infiltration into the VG wall is enhanced under low shear conditions, and this increase is independent of changes in MCP-1 or CCR2 expression. Interruption of the CCR2/MCP-1 pathway leads to attenuated IH development only under low shear conditions. Taken together, these experiments support a novel concept for the “shear stress response element” (SSRE). Rather than a response based largely on biologic perturbations induced by shear (e.g. changes in gene expression), the SSRE phenotypically stems from complex interplay of the biologic and physical microenvironments during vascular remodeling.