title: Nitric Oxide Increases Arterial Endotheial Permeability through Mediating VE-Cadherin Expression during Arteriogenesis.
abstract: Macrophage invasion is an important event during arteriogenesis, but the underlying mechanism is still only partially understood. The present study tested the hypothesis that nitric oxide (NO) and VE-cadherin, two key mediators for vascular permeability, contribute to this event in a rat ischemic hindlimb model. In addition, the effect of NO on expression of VE-caherin and endothelial permeability was also studied in cultured HUVECs. We found that: 1) in normal arteriolar vessels (NAV), eNOS was moderately expressed in endothelial cells (EC) and iNOS was rarely detected. In contrast, in collateral vessels (CVs) induced by simple femoral artery ligation, both eNOS and iNOS were significantly upregulated (P<0.05). Induced iNOS was found mainly in smooth muscle cells, but also in other vascular cells and macrophages; 2) in NAV VE-cadherin was strongly expressed in EC. In CVs, VE-cadherin was significantly downregulated, with a discontinuous and punctate pattern. Administration of nitric oxide donor DETA NONOate (NONOate) further reduced the amounts of Ve-cadherin in CVs, whereas NO synthase inhibitor L-NAME inhibited downregulation of VE-cadherin in CVs; 3) in normal rats Evans blue extravasation (EBE) was low in the musculus gracilis, FITC-dextron leakage was not detected in the vascular wall and few macrophages were observed in perivascular space. In contrast, EBE was significantly increased in femoral artery ligation rats, FITC-dextron leakage and increased amounts of macrophages were detected in CVs, which were further enhanced by administration of NONOate, but inhibited by L-NAME supplement; 4) in vitro experiments confirmed that an increase in NO production reduced VE-cadherin expression, correlated with increases in the permeability of HUVECs. In conclusion, our data for the first time reveal the expression profile of VE-cadherin and alterations of vascular permeability in CVs, suggesting that NO-mediated VE-cadherin pathway may be one important mechanism responsible, at least in part, for macrophage invasion during arteriogenesis.
authors.affiliation: Department of Histology & Embryology, School of Basic Medicine, Central South Univ., Changsha, 410078, Hunan, P.R. China; Department of Anatomy, School of Basic Medicine, Nanchang Univ., Nanchang, 330006, Jiangxi, P.R. China.
authors.forename: Baolin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Dept. of Intensive Care Unit, the 3rd Xiangya Hospital, Central South Univ., Changsha, 410013, Hunan, P.R. China.
authors.forename: Baizhen
authors.initials: B
authors.lastname: Cai
authors.affiliation: Department of Histology & Embryology, School of Basic Medicine, Central South Univ., Changsha, 410078, Hunan, P.R. China.
authors.forename: Panyue
authors.initials: P
authors.lastname: Deng
authors.affiliation: Department of Anatomy & Neurobiology, School of Basic Medicine, Central South Univ., Changsha, 410013, Hunan, P.R. China.
authors.forename: Xiaoqiong
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Histology & Embryology, School of Basic Medicine, Central South Univ., Changsha, 410078, Hunan, P.R. China.
authors.forename: Yinglu
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Histology & Embryology, School of Basic Medicine, Central South Univ., Changsha, 410078, Hunan, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Histology & Embryology, School of Basic Medicine, Central South Univ., Changsha, 410078, Hunan, P.R. China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Cai
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Arteriogenesis Research Group, Bad Nauheim, D-61231, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Schaper
authors.affiliation: Max-Planck-Institute for Heart and Lung Research, Arteriogenesis Research Group, Bad Nauheim, D-61231, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schaper
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D018929:Cell Culture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D009603:Nitroso Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D004791:Enzyme Inhibitors; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009603:Nitroso Compounds; D000099152:Cadherin 5; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat