CD36 mediates endothelial dysfunction downstream of circulating factors induced by O3 exposure.

Inhaled pollutants induce the release of vasoactive factors into the systemic circulation, but little information is available regarding the nature of these factors or their receptors. The pattern recognition receptor CD36 interacts with many damage-related circulating molecules, leading to activation of endothelial cells and promoting vascular inflammation; therefore, we hypothesized that CD36 plays a pivotal role in mediating cross talk between inhaled ozone (O3)-induced circulating factors and systemic vascular dysfunction. O3 exposure (1 ppm × 4h) induced lung inflammation in wild-type (WT) mice, which was absent in the CD36 deficient (CD36(-/-)) mice. Acetylcholine (ACh)-evoked vasorelaxation was impaired in isolated aortas from O3-exposed WT mice but not in vessels from CD36(-/-) mice. To delineate whether vascular impairments were caused by lung inflammation or CD36-mediated generation of circulating factors, naïve aortas were treated with diluted serum from control or O3-exposed WT mice, which recapitulated the impairments of vasorelaxation observed after inhalation exposures. Aortas from CD36(-/-) mice were insensitive to the effects of O3-induced circulating factors, with robust vasorelaxation responses in the presence of serum from O3-exposed WT mice. Lung inflammation was not a requirement for production of circulating vasoactive factors, as serum from O3-exposed CD36(-/-) mice could inhibit vasorelaxation in naïve WT aortas. These results suggest that O3 inhalation induces the release of circulating bioactive factors capable of impairing vasorelaxation to ACh via a CD36-dependent signaling mechanism. Although lung inflammatory and systemic vascular effects were both dependent on CD36, the presence of circulating factors appears to be independent of CD36 and inflammatory responses.

Hepatocyte growth factor/scatter factor promotes retinal angiogenesis through increased urokinase expression.

PURPOSE: The purpose of this study was to determine the role of hepatocyte growth factor (HGF) and c-Met in the initiation and development of retinal neovascularization and to determine whether inhibition of this system can suppress the extent of angiogenesis in an animal model. METHODS: Retinal tissues from animals with oxygen-induced neovascularization were analyzed for HGF and c-Met expression and localization. The effect of HGF on the migratory and invasive behavior of isolated retinal endothelial cells was quantitated, and the role of the extracellular proteinase urokinase in facilitating this process was determined. Mice were treated with intraocular injections of anti-c-Met antibody, and the extent of neovascularization was quantitated. RESULTS: HGF and c-Met were upregulated in the retinas of mice with hypoxia-induced retinal neovascularization. HGF was active, as evidenced by the increased presence of the phosphorylated form of c-Met in the tissues. c-Met was localized to various cell types in the retina, including vascular cells, and HGF was produced by cells in the ganglion and inner nuclear layers. HGF stimulated the secretion of urokinase and its receptor, uPAR, in isolated retinal endothelial cells. HGF increased the migratory and invasive capacity of these cells, which could be inhibited by the disruption of urokinase/uPAR interactions with the A6 peptide. Inhibition of c-Met activation in vivo resulted in a 70% decrease in retinal angiogenesis and a 40% decrease in urokinase activity in the retina. CONCLUSIONS: These studies suggest that HGF may play an important role in the initial stages of retinal angiogenesis by stimulating a migratory phenotype in endothelial cells mediated by increased urokinase activity.