title: Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension.
abstract: OBJECTIVE
  Toll-like receptor 4 (TLR4) signalling contributes to inflammatory cardiovascular diseases, but its role in hypertension and the associated vascular damage is not known. We investigated whether TLR4 activation contributed to angiotensin II (AngII)-induced hypertension and the associated vascular structural, mechanical and functional alterations.
  
  
  METHODS
  AngII was infused (1.44 mg · kg(-1) · day(-1), s.c.) for 2 weeks in C57BL6 mice, treated with a neutralizing anti-TLR4 antibody or IgG (1 μg · day(-1); systolic BP (SBP) and aortic cytokine levels were measured. Structural, mechanical and contractile properties of aortic and mesenteric arterial segments were measured with myography and histology. RT-PCR and Western blotting were used to analyse these tissues and cultured vascular smooth muscle cells (VSMC) from hypertensive rats (SHR).
  
  
  RESULTS
  Aortic TLR4 mRNA levels were raised by AngII infusion. Anti-TLR4 antibody treatment of AngII-treated mice normalised: (i) increased SBP and TNF-α, IL-6 and CCL2 levels; (ii) vascular structural and mechanical changes; (iii) altered aortic phenylephrine- and ACh-induced responses; (iv) increased NOX-1 mRNA levels, superoxide anion production and NAD(P)H oxidase activity and effects of catalase, apocynin, ML-171 and Mito-TEMPO on vascular responses; and (v) reduced NO release and effects of L-NAME on phenylephrine-induced contraction. In VSMC, the MyD88 inhibitor ST-2825 reduced AngII-induced NAD(P)H oxidase activity. The TLR4 inhibitor CLI-095 reduced AngII-induced increased phospho-JNK1/2 and p65 NF-κB subunit nuclear protein expression.
  
  
  CONCLUSIONS
  TLR4 up-regulation by AngII contributed to the inflammation, endothelial dysfunction, vascular remodelling and stiffness associated with hypertension by mechanisms involving oxidative stress. MyD88-dependent activation and JNK/NF-κB signalling pathways participated in these alterations.
authors.affiliation: Dept. of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.|Instituto de Investigación Hospital Universitario La Paz (IdiPaz), Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Hernanz
authors.affiliation: Instituto de Investigación Hospital Universitario La Paz (IdiPaz), Madrid, Spain.|Dept. of Farmacología, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Martínez-Revelles
authors.affiliation: Dept. of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.|Instituto de Investigación Hospital Universitario La Paz (IdiPaz), Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Palacios
authors.affiliation: Dept. of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.|Instituto de Investigación Hospital Universitario La Paz (IdiPaz), Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Martín
authors.affiliation: Dept. of Fisiología, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Cachofeiro
authors.affiliation: Instituto de Investigación Hospital Universitario La Paz (IdiPaz), Madrid, Spain.|Dept. of Farmacología, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Aguado
authors.affiliation: Instituto de Investigación Hospital Universitario La Paz (IdiPaz), Madrid, Spain.|Dept. of Farmacología, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: García-Redondo
authors.affiliation: Dept. of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.
authors.forename: M T
authors.initials: MT
authors.lastname: Barrús
authors.affiliation: Dept. of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.
authors.forename: P R
authors.initials: PR
authors.lastname: de Batista
authors.affiliation: Instituto de Investigación Hospital Universitario La Paz (IdiPaz), Madrid, Spain.|Dept. of Farmacología, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: A M
authors.initials: AM
authors.lastname: Briones
authors.affiliation: Instituto de Investigación Hospital Universitario La Paz (IdiPaz), Madrid, Spain.|Dept. of Farmacología, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Salaices
authors.affiliation: Dept. of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain.
authors.forename: M J
authors.initials: MJ
authors.lastname: Alonso
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure; D004730:Endothelium, Vascular / Q000473:pathology; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007249:Inflammation / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D000804:Angiotensin II