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

• Published in: Journal of vascular surgery 2011-03, Vol.53 (3), p.754-763
• Main Authors: Raman, Kathleen G., MD, MPH, Gandley, Robin E., PhD, Rohland, Jennifer, BS, Zenati, Mazen S., PhD, Tzeng, Edith, MD
• Format: Article
• Language: English
• Subjects: Animals; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis - etiology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Atherosclerosis - physiopathology; Atherosclerosis - prevention & control; Biological and medical sciences; Carotid Artery Injuries - complications; Carotid Artery Injuries - metabolism; Carotid Artery Injuries - pathology; Carotid Artery Injuries - physiopathology; Carotid Artery, Common - drug effects; Carotid Artery, Common - metabolism; Carotid Artery, Common - pathology; Carotid Artery, Common - physiopathology; Cell Proliferation; Cells, Cultured; Cholesterol - blood; Disease Models, Animal; Dose-Response Relationship, Drug; Hypercholesterolemia - complications; Hypercholesterolemia - metabolism; Hypercholesterolemia - pathology; Hypercholesterolemia - physiopathology; Lipoproteins, LDL - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - physiopathology; Myocytes, Smooth Muscle - enzymology; Nitric Oxide - metabolism; Nitric Oxide Synthase Type II - biosynthesis; Nitric Oxide Synthase Type II - genetics; Rats; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Time Factors; Transfection; Traumas. Diseases due to physical agents; Triglycerides - blood; Vascular injuries: limbs, aorta, vena cava; Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels; Vasodilation - drug effects; Vasodilator Agents - pharmacology
• ISSN: 0741-5214; 1097-6809
• DOI: 10.1016/j.jvs.2010.09.038

Objective Atherosclerosis results in vasomotor dysfunction, in part, through impairment of nitric oxide (NO) dependent vasodilation. It is unclear whether blood vessels are dysfunctional in an early environment of hypercholesterolemia alone and if this contributes to the vascular injury response. We hypothesize that early hypercholesterolemia, prior to gross vascular changes, contributes to vasomotor dysfunction and the vascular injury response. The efficacy of NO therapy to protect against the injury response in this setting was also assessed. Methods The effect of oxidized low density lipoprotein (oxLDL) and inducible NO synthase (iNOS) gene transfer on rat aortic smooth muscle cell (SMC) proliferation was measured with3 H-thymidine incorporation. Common carotid arteries (CCA) from wild-type C57BL6 (WT or C57) and apolipoprotein E deficient (ApoE KO) mice fed normal or Western diets for 6 to 8 weeks were tested for vasomotor function using an arteriograph system. Studies were repeated after CCA injury. The effect of iNOS gene transfer on morphometry by histology and vasomotor responses in injured CCAs in ApoE KO was examined. Results OxLDL increased SMC proliferation by >50%. In SMC expressing iNOS, NO production was unaffected by oxLDL and reduced oxLDL and still inhibited SMC proliferation. Endothelium dependent vasorelaxation was reduced in uninjured CCAs from ApoE KO and C57 mice on the Western vs normal diet (ApoE 39% ± 2% vs 55% ± 13%; C57 50% ± 13% vs 76% ± 5%, P < .001) and was increased with longer durations of hypercholesterolemia. Endothelium-dependent and independent vasodilator responses were severely disrupted in C57 and ApoE KO mice 2 weeks following CCA injury but both recovered by 4 weeks. CCA injury in ApoE KO mice resulted in the formation of atheromatous lesions while C57 mice showed no change (intima 27,795 ± 1829 vs 237 ± 28 μm2 ; media 46,306 ± 2448 vs 11,714 ± 392 μm2 , respectively; P < .001). This structural change in the ApoE KO reduced distensibility and increased stiffness. Finally, iNOS gene transfer to injured CCA in ApoE KO mice dramatically reduced atheromatous neointimal lesion formation. Conclusions Early hypercholesterolemia impairs endothelial function, with severity being related to duration and magnitude of hypercholesterolemia. Severe hypercholesterolemia leads to atheromatous lesion formation following injury and stresses the role of vascular injury in atherogenesis and suggests different mechanisms are involved i