title: Interleukin-10 released by CD4(+)CD25(+) natural regulatory T cells improves microvascular endothelial function through inhibition of NADPH oxidase activity in hypertensive mice.
abstract: OBJECTIVE
  We previously demonstrated that a reduced number of CD(4+)CD(25+)-regulatory T cells (Tregs) was associated with microvascular dysfunction in hypertension. However, the underlying mechanism by which Tregs regulate vascular endothelial function remains unknown.
  
  
  RESULTS
  Control and interleukin (IL)-10(-/-) knockout mice were infused with angiotensin II (400 ng/kg/min) for 2 weeks (hypertensive [HT] and HT-IL-10(-/-)). Endothelium-dependent relaxation (EDR) in response to acetylcholine was significantly reduced in mesenteric resistance artery (MRA) from HT and HT-IL-10(-/-) compared with control and IL-10(-/-) mice. Importantly, the incubation of MRA from HT mice with the conditioned media of cultured Tregs, isolated from control mice, reduced NADPH oxidase activity and improved EDR, whereas no effect was observed in MRA from control mice incubated with the same media. These effects were reversed when MRAs were preincubated with IL-10 antibody or IL-10 receptor antagonist, whereas incubation with transforming growth factor-β receptor antagonist had no effect. The transfer of cultured Tregs, isolated from control mice, into HT-IL-10(-/-) mice reduced systolic blood pressure (SBP) and NADPH oxidase activity and improved EDR in MRA compared with untreated HT-IL-10(-/-) mice. In vivo treatment of HT mice with IL-10 (1000 ng/mouse) significantly reduced SBP and NADPH oxidase activity and improved EDR in MRA compared with untreated HT mice. The transfer of cultured Tregs, isolated from IL-10(-/-) mice, into HT mice did not reduce SBP or NADPH oxidase activity or improve EDR. The incubation of MRA from HT mice with apocynin improved EDR, whereas NADPH oxidase substrate attenuated EDR in MRA from control mice, which was reversed with exogenous IL-10.
  
  
  CONCLUSIONS
  These data demonstrate that IL-10 released from Tregs attenuates NADPH oxidase activity, which is a critical process in the improvement of microvascular endothelial function in hypertension, suggesting that Tregs/IL-10 could be a therapeutic target for treatment of vasculopathy in hypertension.
authors.affiliation: Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Modar
authors.initials: M
authors.lastname: Kassan
authors.forename: Maria
authors.initials: M
authors.lastname: Galan
authors.forename: Megan
authors.initials: M
authors.lastname: Partyka
authors.forename: Mohamed
authors.initials: M
authors.lastname: Trebak
authors.forename: Khalid
authors.initials: K
authors.lastname: Matrougui
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000009:adverse effects; D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism*; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000502:physiology*; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000502:physiology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D014665:Vasodilator Agents; D000804:Angiotensin II; D016753:Interleukin-10; D019255:NADPH Oxidases; D000109:Acetylcholine