TLR4 regulates pulmonary vascular homeostasis and remodeling via redox signaling.

Academic Article


  • Pulmonary arterial hypertension (PAH) contributes to morbidity and mortality of patients with lung and heart diseases. We demonstrated that hypoxia induced PAH and increased pulmonary arterial wall thickness in wild-type mice. Mice deficient in toll-like receptor 4 (TLR4-/-) spontaneously developed PAH, which was not further enhanced by hypoxia. Echocardiography determined right ventricular hypertrophy and decreased pulmonary arterial acceleration time were associated with the development of PAH in TLR4(-/-) mice. In pulmonary arterial smooth muscle cells (PASMC), hypoxia decreased TLR4 expression and induced reactive oxygen species (ROS) and Nox1/Nox4. Inhibition of NADPH oxidase decreased hypoxia-induced proliferation of wild-type PASMC. PASMC derived from TLR4(-/-) mice exhibited increased ROS and Nox4/Nox1 expression. Our studies demonstrate an important role of TLR4 in maintaining normal pulmonary vasculature and in hypoxia-induced PAH. Inhibition of TLR4, by genetic ablation or hypoxia, increases the expression of Nox1/Nox4 and induces PASMC proliferation and vascular remodeling. These results support a novel function of TLR4 in regulating the development of PAH and reveal a new regulatory axis contributing to TLR4 deficiency-induced vascular hypertrophy and remodeling.
  • Published In


  • Animals, Arteries, Hemodynamics, Homeostasis, Hypertension, Pulmonary, Lung, Mice, Muscle, Smooth, Vascular, NADP, Oxidation-Reduction, Reactive Oxygen Species, Signal Transduction, Toll-Like Receptor 4
  • Author List

  • Ma L; Ambalavanan N; Liu H; Sun Y; Jhala N; Bradley WE; Dell'Italia LJ; Michalek S; Wu H; Steele C
  • Start Page

  • 397
  • End Page

  • 409
  • Volume

  • 21