PMID- 21076854 OWN - NLM STAT- MEDLINE DCOM- 20110418 LR - 20231213 IS - 1573-4919 (Electronic) IS - 0300-8177 (Linking) VI - 348 IP - 1-2 DP - 2011 Feb TI - Mesenteric vascular remodeling in hyperhomocysteinemia. PG - 99-108 LID - 10.1007/s11010-010-0643-y [doi] AB - Remodeling by its very nature implies synthesis and degradation of extracellular matrix components (such as elastin, collagen, and connexins). Most of the vascular matrix metalloproteinase (MMP) are latent because of the presence of constitutive nitric oxide (NO). However, during oxidative stress peroxinitrite (ONOO-) activates the latent MMPs and instigates vascular remodeling. Interestingly, in mesenteric artery, homocysteine (Hcy) decreases the NO bio-availability, and folic acid (FA, an Hcy-lowering agent) mitigates the Hcy-mediated mesentery artery dysfunction. Dimethylarginine dimethylaminohydrolase-2 (DDAH-2) and endothelial nitric oxide synthase (eNOS) increases NO production. The hypothesis was that the Hcy decreased NO bio-availability, in part, activating MMP, decreasing elastin, DDAH-2, eNOS and increased vasomotor response by increasing connexin. To test this hypothesis,the authors used 12-week-old C57BJ/L6 wild type (WT) and hyperhomocysteinemic (HHcy)-cystathione beta synthase heterozygote knockout (CBS+/-) mice. Blood pressure measurements were made by radio-telemetry. WT and MMP-9 knockout mice were administered with Hcy (0.67 mg/ml in drinking water). Superior mesenteric artery and mesenteric arcade were analyzed with light and confocal microscopy. The protein expressions were measured by western blot analysis. The mRNA levels for MMP-9 were measured by RT-PCR. The data showed decreased DDAH-2 and eNOS expressions in mesentery in CBS-/+ mice compared with WT mice. Immuno-fluorescence and western blot results suggest increased MMP-9 and connexin-40 expression in mesenteric arcades of CBS-/+ mice compared with WT mice. The wall thickness of third-order mesenteric artery was increased in CBS-/+ mice compared to WT mice. Hcy treatment increased blood pressure in WT mice. Interestingly, in MMP-9 KO, Hcy did not increase blood pressure. These results may suggest that HHcy causes mesenteric artery remodeling and narrowing by activating MMP-9 and decreasing DDAH-2 and eNOS expressions, compromising the blood flow, instigating hypertension, and acute abdomen pain. FAU - Munjal, C AU - Munjal C AD - Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY 40202, USA. FAU - Givvimani, S AU - Givvimani S FAU - Qipshidze, N AU - Qipshidze N FAU - Tyagi, N AU - Tyagi N FAU - Falcone, J C AU - Falcone JC FAU - Tyagi, S C AU - Tyagi SC LA - eng GR - HL-71010/HL/NHLBI NIH HHS/United States GR - NS-51568/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20101113 PL - Netherlands TA - Mol Cell Biochem JT - Molecular and cellular biochemistry JID - 0364456 RN - 0 (Connexins) RN - 0 (Extracellular Matrix Proteins) RN - 0 (Nitrites) RN - 0 (RNA, Messenger) RN - 0LVT1QZ0BA (Homocysteine) RN - 9007-58-3 (Elastin) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 1.14.13.39 (Nos3 protein, mouse) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.4.24.35 (Mmp9 protein, mouse) RN - EC 3.5.- (Amidohydrolases) RN - EC 3.5.3.18 (dimethylargininase) RN - EC 4.2.1.22 (Cystathionine beta-Synthase) SB - IM MH - Abdominal Pain/etiology MH - Amidohydrolases/metabolism MH - Animals MH - Blood Pressure MH - Blood Pressure Monitoring, Ambulatory MH - Blotting, Western MH - Connexins/metabolism MH - Cystathionine beta-Synthase/genetics/metabolism MH - Disease Models, Animal MH - Elasticity MH - Elastin/metabolism MH - Extracellular Matrix Proteins/*metabolism MH - Fluorescent Antibody Technique MH - Homocysteine MH - Hyperhomocysteinemia/chemically induced/genetics/*metabolism/pathology/physiopathology MH - Hypertension/genetics/*metabolism/pathology/physiopathology MH - Male MH - Matrix Metalloproteinase 9/deficiency/genetics MH - Mesenteric Artery, Superior/*metabolism/pathology/physiopathology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Microscopy, Confocal MH - Microscopy, Video MH - Nitric Oxide Synthase Type III/metabolism MH - Nitrites/metabolism MH - RNA, Messenger/metabolism MH - Reverse Transcriptase Polymerase Chain Reaction MH - Splanchnic Circulation MH - Telemetry MH - Vascular Resistance MH - Gap Junction alpha-5 Protein EDAT- 2010/11/16 06:00 MHDA- 2011/04/19 06:00 CRDT- 2010/11/16 06:00 PHST- 2010/06/29 00:00 [received] PHST- 2010/10/28 00:00 [accepted] PHST- 2010/11/16 06:00 [entrez] PHST- 2010/11/16 06:00 [pubmed] PHST- 2011/04/19 06:00 [medline] AID - 10.1007/s11010-010-0643-y [doi] PST - ppublish SO - Mol Cell Biochem. 2011 Feb;348(1-2):99-108. doi: 10.1007/s11010-010-0643-y. Epub 2010 Nov 13.