Increased oxidized low‐density lipoprotein causes blood‐brain barrier disruption in early‐onset preeclampsia through LOX‐1

Abstract

Early-onset preeclampsia (EPE) is a severe form of preeclampsia that involves life-threatening neurological complications. However, the underlying mechanism by which EPE affects the maternal brain is not known. We hypothesized that plasma from women with EPE increases blood-brain barrier (BBB) permeability vs. plasma from women with late-onset preeclampsia (LPE) or normal pregnancy (NP) and investigated its underlying mechanism by perfusing cerebral veins from nonpregnant rats (n=6-7/group) with human plasma from women with EPE, LPE, or NP and measuring permeability. We show that plasma from women with EPE significantly increased BBB permeability vs. plasma from women with LPE or NP (P<0.001). BBB disruption in response to EPE plasma was due to a 260% increase of circulating oxidized LDL (oxLDL) binding to its receptor, LOX-1, and subsequent generation of peroxynitrite (P<0.001). A rat model with pathologically high lipid levels in pregnancy showed symptoms of preeclampsia, including elevated blood pressure, growth-restricted fetuses, and LOX-1-dependent BBB disruption, similar to EPE (P<0.05). Thus, we have identified LOX-1 activation by oxLDL and subsequent peroxynitrite generation as a novel mechanism by which disruption of the BBB occurs in EPE. As increased BBB permeability is a primary means by which seizure and other neurological symptoms ensue, our findings highlight oxLDL, LOX-1, and peroxynitrite as important therapeutic targets in EPE.

Formerly eclamptic women have lower nonpregnant blood pressure compared with formerly pre‐eclamptic women: a retrospective cohort study

“…Circulating factors have shown to increase BBB permeability and seizure activity 17, 18 . For example, preeclampsia is associated with an superimposed dyslipidemia compared to normal pregnancy 29, 30, 31 .…”

“…For example, preeclampsia is associated with an superimposed dyslipidemia compared to normal pregnancy 29, 30, 31 . Recent studies demonstrated that elevated levels of oxLDL increase BBB permeability and may be an important contributor to vasogenic brain edema in severe early-onset preeclampsia 17, 32 . Our results suggest that antepartum eclampsia occurs more often in early-onset preeclampsia, however, did not indicate that eclamptic women already had an underlying metabolic disorder.…”

Inhibition of Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 Protects against Plasma/Hypoxia-Mediated Trophoblast Dysfunction Associated with Preeclampsia

“…Several lines of evidence have suggested that oxLDL exhibits a wide range of biological effects on cultured cells. Increased circulating levels of oxLDL in PE have been shown in several [30,31], but not all studies [32]. LOX-1 is an endothelial receptor for circulating oxLDL and has been studied extensively in pathological states such as atherosclerosis, diabetes, coronary arterial heart disease, and hypertension [33].…”

Lipids and Diabetic Retinopathy

“…[44][45][46] These modified particles are cytotoxic to all retinal cell types, including capillary cells in the BRB (thus creating a positive feedback process in which transient leakiness of the BRB leads to chronic damage). 40,41,[47][48][49][50] Thus, serum lipid profile may be less important, and weakening of the BRB may be a prerequisite for local lipoprotein-mediated damage.…”