title: 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.
authors.affiliation: Department of Neurology, University of Vermont College of Medicine, Burlington, VT 05405, USA.
authors.forename: Malou P H
authors.initials: MP
authors.lastname: Schreurs
authors.forename: Carl A
authors.initials: CA
authors.lastname: Hubel
authors.forename: Ira M
authors.initials: IM
authors.lastname: Bernstein
authors.forename: Arun
authors.initials: A
authors.lastname: Jeyabalan
authors.forename: Marilyn J
authors.initials: MJ
authors.lastname: Cipolla
mesh_terms: D000328:Adult; D000818:Animals; D001794:Blood Pressure; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology; D002199:Capillary Permeability; D002560:Cerebrovascular Circulation; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood / Q000503:physiopathology; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood*; D030421:Peroxynitrous Acid / Q000097:blood; D011225:Pre-Eclampsia / Q000097:blood / Q000503:physiopathology; D011247:Pregnancy; D011263:Pregnancy Trimester, Third / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051127:Scavenger Receptors, Class E / Q000097:blood*
chemical_list: D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; C495136:OLR1 protein, rat; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D030421:Peroxynitrous Acid