Inhibition of Lectin-Like Oxidized Low-Density Lipoprotein-1 Receptor Protects Against Plasma-Mediated Vascular Dysfunction Associated With Pre-Eclampsia

Abstract

Pre-eclampsia (PE) is associated with vascular endothelial dysfunction and oxidative stress initiated by impaired trophoblast invasion. Oxidative stress modifies circulating low-density lipoprotein (LDL) to oxidized LDL (oxLDL). Lectin-like oxLDL receptor-1 (LOX-1) is a scavenger receptor for oxLDL. We hypothesized that plasma from patients with PE alters LOX-1 in normal human vessels during pregnancy, causing oxLDL-induced impairment of vascular function. Control-matched plasma was obtained from women with PE (n = 6). Oxidized LDL and soluble LOX-1 levels were determined by enzyme-linked immunoassay (ELISA). Remaining plasma was pooled and stored at -80ºC. Human omental arteries were incubated in 3% plasma from normal pregnant (NP) women or plasma from women with PE. Expression of LOX-1 in these vessels was determined by immunohistochemistry with antibodies against LOX-1. The omental vessels were exposed to oxLDL and the LOX-1 inhibitor TS20. Vascular function was assessed in response to the vasoconstrictor U46619 and the vasodilators bradykinin (BK) and sodium nitroprusside (SNP). No significant differences in the concentrations of oxLDL or soluble LOX-1 (sLOX-1) were found in plasma from women with PE as compared with NP women. The expression of LOX-1 was not significantly different in either the NP or PE incubated omental vessels. Incubation of vessels from NP women in plasma from women with PE impaired their relaxation in response to BK as compared with that of NP vessels incubated in plasma from NP women. Exposure to oxLDL further impaired relaxation in NP vessels incubated with plasma from women with PE. Inhibition of LOX-1 protected against the impairment of vascular relaxation induced by plasma from women with PE. Inhibition of LOX-1 prevents endothelial dysfunction in an in vitro model of PE and may prove useful as a therapeutic target in the treatment of PE.