Toll-like receptor 4 contributes to vascular remodelling and endothelial dysfunction in angiotensin II-induced hypertension

Br J Pharmacol. 2015 Jun;172(12):3159-76. doi: 10.1111/bph.13117. Epub 2015 Apr 10.

Abstract

Background and purpose: 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.

Experimental approach: 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).

Key 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 and implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / administration & dosage*
  • Animals
  • Aorta / metabolism
  • Blood Pressure
  • Endothelium, Vascular / pathology
  • Hypertension / genetics
  • Hypertension / physiopathology*
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle / metabolism
  • NF-kappa B / metabolism
  • Oxidative Stress / physiology
  • Rats
  • Rats, Inbred SHR
  • Reverse Transcriptase Polymerase Chain Reaction
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*
  • Up-Regulation
  • Vascular Remodeling / physiology*

Substances

  • NF-kappa B
  • Toll-Like Receptor 4
  • Angiotensin II