title: The potential role of leptin in the vascular remodeling associated with obesity.
abstract: OBJECTIVE
  Extracellular matrix (ECM) participates in the vascular remodeling associated with obesity. We investigated the effects of leptin on the production of ECM components in primary cultured vascular smooth muscle cells (VSMCs) and whether leptin could be a mediator of obesity-induced vascular remodeling.
  
  
  METHODS
  T he effects of leptin (100 ng ml(-1)) on ECM components and superoxide anion production (O(2)(.-)) were evaluated in presence or absence of the antioxidant melatonin (10(-)(3) mmol l(-1)) or the inhibitor of phosphatidylinositol 3'-kinase (PI3K), LY294002 (2 × 10(-)(4) mmol l(-1)) in VSMCs from adult rats in order to explore the role of both oxidative stress and the participation of PI3K/Akt pathway in the effects of leptin. ECM components and O(2)(.-) were quantified in the aortic media of male Wistar rats fed a high-fat diet (HFD; 33.5% fat), or a standard diet (CT; 3.5% fat) for 6 weeks.
  
  
  RESULTS
  In VSMCs, leptin enhanced gene and protein levels of collagen I, fibronectin, transforming growth factor (TGF)-β and connective tissue growth factor (CTGF) but did not change those of collagen III and galectin-3. Leptin also increased O(2)(.-) and Akt phosphorylation in VSMCs. These effects were prevented by the presence of either melatonin or LY294002, except O(2)(.-) production in the case of PI3K inhibition. The increase in body weight in HFD rats was accompanied by aorta thickening due to an increase in media area. The aortic fibrosis observed in HFD rats was associated with high levels of leptin, collagen type I, fibronectin, TGF-β, CTGF, phosphorylated Akt and O(2)(.-). Aortic leptin levels were positively correlated with total collagen, collagen I, TGF-β and CTGF levels. No differences were observed in the levels of collagen III, elastin or galectin-3 between both the groups.
  
  
  CONCLUSIONS
  Leptin could participate in the vascular remodeling and stiffness associated with obesity by ECM production in VSMCs through the activation of oxidative stress-PI3K/Akt pathway and the production of the profibrotic factors TGF-β and CTGF.
authors.affiliation: 1] Department of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain [2] Cardiovascular Translational Research, NavarraBiomed (Fundación Miguel Servet), Pamplona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Martínez-Martínez
authors.affiliation: Department of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Miana
authors.affiliation: Department of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Jurado-López
authors.affiliation: Department of Ophthalmology and Oto-Rhino-Laringology, Faculty of Psychology, Universidad Complutense, Madrid, Spain.
authors.forename: M V
authors.initials: MV
authors.lastname: Bartolomé
authors.affiliation: Department of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
authors.forename: F V
authors.initials: FV
authors.lastname: Souza Neto
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria Hospital La Paz (IdiPAz), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Salaices
authors.affiliation: Cardiovascular Translational Research, NavarraBiomed (Fundación Miguel Servet), Pamplona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: López-Andrés
authors.affiliation: Department of Physiology, School of Medicine, Universidad Complutense, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Cachofeiro
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology* / Q000503:physiopathology; D002478:Cells, Cultured; D020738:Leptin / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D066253:Vascular Remodeling
chemical_list: D020738:Leptin