Vasomotor responses to arterial injury in a mouse model of atherosclerosis

Abstract

Introduction: Intimal hyperplasia (IH) limits the success of angioplasty performed for atherosclerotic (ATH) disease. However, therapies to inhibit IH have been studied in normal vessels which may not predict responses in ATH vessels. The purpose of this study was to determine the impact of ATH on vasomotor responses at baseline and following arterial injury in apolipoprotein E deficient (Apo E-/-) mice which develop ATH lesions resembling human disease. Methods: C57BL/6J (C57) (n = 12) and Apo E-/- (n = 8) mice were fed a Western-type (WTD) or chow diet for 12 wks. Reproducible common carotid artery (CCA) injury was created with a 0.014 inch wire. CCAs were isolated at 4 wks. Morphometric analysis and macrophage, smooth muscle (SMC), and lipid staining were performed. Endothelium-dependent vasorelaxation to methacholine was assessed in preconstricted vessels. The ability of each vessel to generate an active contractile response was defined as tone (% change in diameter vs. fully-relaxed diameter). Data were analyzed using ANOVA and significance defined as p < 0.05. Results: Apo E-/- mice had significantly increased intimal (117x, p = 0.0003) and medial (4x, p = 0.006) hyperplasia vs C57 mice after injury. Extensive macrophage, SMC, and lipid deposition was detected in both the media and neointima of Apo E -/- vessels but not C57 mice. Endothelium-dependent relaxation was reduced in uninjured (2x, p = 0.001) and injured arteries (1.7x, p = 0.001) from ApoE -/- vs C57 mice. Injury decreased myogenic tone in Apo E -/- and control mice on chow (4.7x, p = 0.005) or WTD (3.5x, p = 0.004) vs matched uninjured vessels. Conclusions: Vascular injury significantly alters the vasomotor response in wildtype mice. However, ApoE -/- mice have significantly altered vasomotor function at baseline and following injury. Early ATH renders the vessels more susceptible to injury-induced IH and progression of ATH and stress the impact of ATH on vascular function as well as on vascular responses to injury. Potential therapies for IH should also be tested in models of ATH for histologic and physiologic improvement.