PMID- 15578196 OWN - NLM STAT- MEDLINE DCOM- 20081202 LR - 20131121 IS - 1435-1803 (Electronic) IS - 0300-8428 (Linking) VI - 100 IP - 2 DP - 2005 Mar TI - Endothelial nitric oxide synthase gene transfer restores endothelium-dependent relaxations and attenuates lesion formation in carotid arteries in apolipoprotein E-deficient mice. PG - 102-11 AB - Nitric oxide (NO) and monocyte chemoattractant protein-1 (MCP-1) exert partly opposing effects in vascular biology. NO plays pleiotropic vasoprotective roles including vasodilation and inhibition of platelet aggregation, smooth muscle cell proliferation, and endothelial monocyte adhesion, the last effect being mediated by MCP-1 downregulation. Early stages of arteriosclerosis are associated with reduced NO bioactivity and enhanced MCP-1 expression. We have evaluated adenovirus-mediated gene transfer of human endothelial NO synthase (eNOS) and of a N-terminal deletion (8ND) mutant of the MCP-1 gene that acts as a MCP-1 inhibitor in arteriosclerosis-prone, apolipoprotein E-deficient (ApoE(-/-)) mice. Endothelium-dependent relaxations were impaired in carotid arteries instilled with a noncoding adenoviral vector but were restored by eNOS gene transfer (p < 0.01). A perivascular collar was placed around the common carotid artery to accelerate lesion formation. eNOS gene transfer reduced lesion surface areas, intima/media ratios, and macrophage contents in the media at 5-week follow-up (p < 0.05). In contrast, 8ND-MCP-1 gene transfer did not prevent lesion formation. In conclusion, eNOS gene transfer restores endothelium-dependent vasodilation and inhibits lesion formation in ApoE(-/-) mouse carotids. Further studies are needed to assess whether vasoprotection is maintained at later disease stages and to evaluate the long-term efficacy of eNOS gene therapy for primary arteriosclerosis. FAU - Mujynya-Ludunge, Kathi AU - Mujynya-Ludunge K AD - Division of Cardiology, University of Lausanne, Faculty of Biology and Medicine CHUV-BH10, Lausanne, Switzerland. FAU - Viswambharan, Hema AU - Viswambharan H FAU - Driscoll, Robert AU - Driscoll R FAU - Ming, Xiu-Fen AU - Ming XF FAU - von Segesser, Ludwig K AU - von Segesser LK FAU - Kappenberger, Lukas AU - Kappenberger L FAU - Yang, Zhihong AU - Yang Z FAU - Vassalli, Giuseppe AU - Vassalli G LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20041124 PL - Germany TA - Basic Res Cardiol JT - Basic research in cardiology JID - 0360342 RN - 0 (Apolipoproteins E) RN - 0 (CCL2 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (Cholesterol, HDL) RN - 0 (Dietary Fats) RN - 0 (Vasodilator Agents) RN - 97C5T2UQ7J (Cholesterol) RN - EC 1.14.13.39 (NOS3 protein, human) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) SB - IM MH - Adenoviridae/genetics MH - Animals MH - Apolipoproteins E/*deficiency/genetics MH - Carotid Artery Diseases/genetics/metabolism/pathology/physiopathology/*therapy MH - Carotid Artery, Common/drug effects/*enzymology/pathology/physiopathology MH - Chemokine CCL2/genetics/*metabolism MH - Cholesterol/blood MH - Cholesterol, HDL/blood MH - Dietary Fats MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Gene Transfer Techniques MH - *Genetic Therapy MH - Genetic Vectors MH - Humans MH - Macrophages/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mutation MH - Nitric Oxide Synthase Type III/genetics/*metabolism MH - *Vasodilation/drug effects MH - Vasodilator Agents/pharmacology EDAT- 2004/12/04 09:00 MHDA- 2008/12/17 09:00 CRDT- 2004/12/04 09:00 PHST- 2004/04/19 00:00 [received] PHST- 2004/10/20 00:00 [accepted] PHST- 2004/09/22 00:00 [revised] PHST- 2004/12/04 09:00 [pubmed] PHST- 2008/12/17 09:00 [medline] PHST- 2004/12/04 09:00 [entrez] AID - 10.1007/s00395-004-0500-9 [doi] PST - ppublish SO - Basic Res Cardiol. 2005 Mar;100(2):102-11. doi: 10.1007/s00395-004-0500-9. Epub 2004 Nov 24.