Early hypercholesterolemia contributes to vasomotor dysfunction and injury associated atherogenesis that can be inhibited by nitric oxide Kathleen G.

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Presentation transcript:

Early hypercholesterolemia contributes to vasomotor dysfunction and injury associated atherogenesis that can be inhibited by nitric oxide Kathleen G. Raman, MD, MPH, Robin E. Gandley, PhD, Jennifer Rohland, BS, Mazen S. Zenati, PhD, Edith Tzeng, MD Journal of Vascular Surgery Volume 53, Issue 3, Pages 754-763 (March 2011) DOI: 10.1016/j.jvs.2010.09.038 Copyright © 2011 Society for Vascular Surgery Terms and Conditions

Fig 1 Oxidized low density lipoprotein (oxLDL) stimulates smooth muscle cell (SMC) proliferation in vitro. SMC were cultured and oxLDL (50 μg/mL) in growth medium was added to the SMC and proliferation was quantified using 3H-thymidine incorporation over 24 hours (A). Proliferation was expressed as percent of SMC cultured in 10% serum. SMC were also treated with AdiNOS or AdlacZ. The effect of NO with and without oxLDL on SMC proliferation was also assessed. Griess reaction was performed to quantify nitric oxide (NO) production by the SMCs (B). *P < .001 vs all other groups (except AdiNOS + oxLDL vs AdlacZ + oxLDL), †P < .05 vs ApoE KO under the same conditions, ‡P < .001 vs all other groups. Journal of Vascular Surgery 2011 53, 754-763DOI: (10.1016/j.jvs.2010.09.038) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

Fig 2 The vascular injury response is increased in ApoE KO mice compared with C57 mice. Carotid injury was created with a wire and arteries were collected 4 weeks later. Vessels were fixed, sectioned and stained with H&E, and imaged at ×200. A, C57 artery with H&E; B, ApoE KO artery with H&E; C, C57 artery under autofluorescence; D, ApoE KO artery under autofluorescence; E, C57 artery under polarized light; F, ApoE KO artery under polarized light; and G, quantification of intimal and medial arteries (mean of eight sections per artery and eight mice per group, error bars represent SEM), *P < .001 vs C57. Journal of Vascular Surgery 2011 53, 754-763DOI: (10.1016/j.jvs.2010.09.038) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

Fig 3 Vasorelaxation responses of isolated carotid arteries are significantly reduced in (A) intact arteries from mice on Western diet for 8 weeks (open circles and squares; * WT normal diet vs ApoE KO Western, P ≤ .04; # WT normal diet vs WT Western, P ≤ .03; ^ ApoE KO normal diet vs ApoE KO Western, P = .021; + WT normal diet vs ApoE KO normal diet, P = .022) or (B) in the contralateral injured arteries from the same animals (solid circles and squares; * WT normal diet vs ApoE KO Western, P < .001; # ApoE KO normal diet vs ApoE KO Western, P < .001; ^ WT Western vs Apo E KO Western, P ≤ .02; + ApoE KO normal diet vs WT Western, P ≤ .02; % WT normal diet vs WT Western, P = .01). The influence of diet (8 weeks) and injury (4 weeks) on arteries from WT mice is represented in (C) (* normal diet intact vs Western injured, P ≤ .02; + normal diet intact vs Western intact, P ≤ .03), and in arteries from ApoE KO mice in (D) (*normal diet injured vs Western injured, P < .001; + normal diet injured vs Western intact P ≤ .009; − normal diet intact vs Western injured, P < .001; ^ normal diet intact vs Western intact, P ≤ .03; # normal diet injured vs normal diet intact, P = .029). At 2 weeks postinjury, injured carotid arteries from ApoE KO mice on Western diet had E, very little endothelial mediated relaxation (solid circles, *P ≤ .001) and had F, reduced smooth muscle mediated relaxation in response to a nitric oxide donor (solid circles, *P ≤ .001). At 4 weeks postinjury, relaxation to NO donor has recovered (B-D). Journal of Vascular Surgery 2011 53, 754-763DOI: (10.1016/j.jvs.2010.09.038) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

Fig 4 Active and passive properties of isolated carotid arteries. A, Active contractility in response to pressure stimuli (myogenic tone) was lost in injured arteries from ApoE KO mice regardless of diet (solid symbols). Myogenic tone was lost in all injured arteries at both 2 and 4 weeks postinjury (data not shown for 2 weeks or WT mice). *Western intact vs normal diet injured, P ≤ .03; # Western intact vs Western injured, P ≤ .001; ^ normal diet intact vs Western injured, P ≤ .05; + normal diet intact vs normal diet injured, P ≤ .02; % Western intact vs normal diet intact, P = .022. A and B, Distensibility was increased in the injured carotid arteries at 2 weeks postsurgery (solid black squares), while the injured arteries were less distensible than intact carotid arteries regardless of diet at 4 weeks postinjury in ApoE KO mice. *Western 2 WK injured vs Western intact, P < .034; ^ Western 2 WK injured vs Western 2 WK intact, P < .009; # Western 2 WK injured vs Western injured, P < .009; % Western 2 WK intact vs Western injured, P < .001. C, Stress-strain calculations showed that injured arteries after 4 weeks of recovery experienced greater amounts of stress per given strain. *ApoE KO Western injured vs WT Western intact, P ≤ .03; # ApoE KO Western injured vs ApoE KO Western intact, P ≤ .04; ^ ApoE KO Western injured vs WT Western injured, P ≤ .02, + WT Western intact vs WT Western injured, P ≤ .03. Journal of Vascular Surgery 2011 53, 754-763DOI: (10.1016/j.jvs.2010.09.038) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

Fig 5 Inducible nitric oxide synthase (iNOS) gene transfer inhibits intimal and medial hyperplasia in injured carotid arteries (CCA)s. ApoE KO mice underwent wire injury of the carotid artery followed by adventitial gene transfer with AdiNOS or AdlacZ. CCAs were isolated 4 weeks later, sectioned and stained, and imaged at ×200. A, AdlacZ vessel stained with H&E; B, AdiNOS vessel stained with H&E; C, AdlacZ vessel under autofluorescence; D, AdiNOS vessel under autofluorescence; E, AdiNOS vessel stained for β-galactosidase with X-gal; F, AdlacZ stained with X-gal; and G, morphometric analysis of intimal and medial areas (eight semi-serial sections/vessel, eight animals per group, *P < .001 vs AdlacZ). Journal of Vascular Surgery 2011 53, 754-763DOI: (10.1016/j.jvs.2010.09.038) Copyright © 2011 Society for Vascular Surgery Terms and Conditions

Fig 6 Inducible nitric oxide synthase (iNOS) gene transfer does not accelerate vasomotor recovery following injury. ApoE KO mice on Western diet underwent wire injury of the carotid artery (CCA) followed by adventitial gene transfer with AdiNOS or AdlacZ. CCAs were isolated 2 weeks later for vasorelaxation to methacholine studies, and data are presented in comparison to untransfected intact and injured arteries from ApoE KO mice at same time point. Methacholine response curve shows poor endothelium dependent vasorelaxation in all injury groups. Journal of Vascular Surgery 2011 53, 754-763DOI: (10.1016/j.jvs.2010.09.038) Copyright © 2011 Society for Vascular Surgery Terms and Conditions