Regulation of lymphatic function and injury by nitrosative stress in obese mice.
Regulation of lymphatic function and injury by nitrosative stress in obese mice.
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DOI：
10.1016/j.molmet.2020.101081
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发表时间：
2020-12
影响因子：
8.1
通讯作者：
Mehrara BJ
中科院分区：
文献类型：
--
作者：
Rehal S;Kataru RP;Hespe GE;Baik JE;Park HJ;Ly C;Shin J;Mehrara BJ
Obesity results in lymphatic dysfunction, but the cellular mechanisms that mediate this effect remain largely unknown. Previous studies in obese mice have shown that inducible nitric oxide synthase-expressing (iNOS+) inflammatory cells accumulate around lymphatic vessels. In the current study, we therefore tested the hypothesis that increased expression of iNOS results in nitrosative stress and injury to the lymphatic endothelial cells (LECs). In addition, we tested the hypothesis that lymphatic injury, independent of obesity, can modulate glucose and lipid metabolism. We compared the metabolic changes and lymphatic function of wild-type and iNOS knockout mice fed a normal chow or high-fat diet for 16 weeks. To corroborate our in vivo findings, we analyzed the effects of reactive nitrogen species on isolated LECs. Finally, using a genetically engineered mouse model that allows partial ablation of the lymphatic system, we studied the effects of acute lymphatic injury on glucose and lipid metabolism in lean mice. The mesenteric lymphatic vessels of obese wild-type animals were dilated, leaky, and surrounded by iNOS+ inflammatory cells with resulting increased accumulation of reactive nitrogen species when compared with lean wild-type or obese iNOS knockout animals. These changes in obese wild-type mice were associated with systemic glucose and lipid abnormalities, as well as decreased mesenteric LEC expression of lymphatic-specific genes, including vascular endothelial growth factor receptor 3 (VEGFR-3) and antioxidant genes as compared with lean wild-type or obese iNOS knockout animals. In vitro experiments demonstrated that isolated LECs were more sensitive to reactive nitrogen species than blood endothelial cells, and that this sensitivity was ameliorated by antioxidant therapies. Finally, using mice in which the lymphatics were specifically ablated using diphtheria toxin, we found that the interaction between metabolic abnormalities caused by obesity and lymphatic dysfunction is bidirectional. Targeted partial ablation of mesenteric lymphatic channels of lean mice resulted in increased accumulation of iNOS+ inflammatory cells and increased reactive nitrogen species. Lymphatic ablation also caused marked abnormalities in insulin sensitivity, serum glucose and insulin concentrations, expression of insulin-sensitive genes, lipid metabolism, and significantly increased systemic and mesenteric white adipose tissue (M-WAT) inflammatory responses. Our studies suggest that increased iNOS production in obese animals plays a key role in regulating lymphatic injury by increasing nitrosative stress. In addition, our studies suggest that obesity-induced lymphatic injury may amplify metabolic abnormalities by increasing systemic and local inflammatory responses and regulating insulin sensitivity. These findings suggest that manipulation of the lymphatic system may represent a novel means of treating metabolic abnormalities associated with obesity. Increased iNOS+ cells around mesenteric lymphatics of high fat diet-induced obese mice. iNOS knockout mice are protected from obesity-induced lymphatic dysfunction. Lymphatic endothelial cells are highly sensitive to nitrosative stress. Nitrosative stress causes lymphatic gene regulation. Lymphatic injury alone enhances iNOS+ cells and causes insulin resistance and dyslipidemia.
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影响因子：
2.9
作者：
GREEN, LC;WAGNER, DA;TANNENBAUM, SR
通讯作者：
TANNENBAUM, SR
影响因子：
5.5
作者：
Gasheva, Olga Yu.;Zawieja, David C.;Gashev, Anatoliy A.
通讯作者：
Gashev, Anatoliy A.
DOI：
10.1111/micc.12364
发表时间：
2017-04
期刊：
Microcirculation (New York, N.Y. : 1994)
影响因子：
--
作者：
Chen Y;Rehal S;Roizes S;Zhu HL;Cole WC;von der Weid PY
通讯作者：
von der Weid PY
影响因子：
3.7
作者：
Blum KS;Karaman S;Proulx ST;Ochsenbein AM;Luciani P;Leroux JC;Wolfrum C;Detmar M
通讯作者：
Detmar M
影响因子：
4.6
作者：
Kasuya A;Sakabe J;Tokura Y
通讯作者：
Tokura Y