High-cholesterol diet during pregnancy induces maternal vascular dysfunction in mice: potential role for oxidized LDL-induced LOX-1 and AT1 receptor activation

Abstract

The lectin-like oxidized low-density-lipoprotein (oxLDL) receptor-1 (LOX-1) has been shown to induce angiotensin II (AngII) type 1 receptor (AT1) activation, contributing to vascular dysfunction. Preeclampsia is a pregnancy complication characterized by vascular dysfunction and increased LOX-1 and AT1 activation; however, whether LOX-1 and AT1 activity contributes to vascular dysfunction in preeclampsia is unknown. We hypothesized that increased oxLDL levels during pregnancy lead to LOX-1 activation and subsequent AT1 activation, resulting in vascular dysfunction. Pregnant wild-type (WT) and transgenic LOX-1 overexpressing (LOX-1tg) mice were fed a control diet (CD) or high-cholesterol diet (HCD, to impair vascular function) between gestational day (GD) 13.5-GD18.5. On GD18.5, AngII-induced vasoconstriction and methylcholine (MCh)-induced endothelium-dependent vasodilation responses were assessed in aortas and uterine arteries. HCD decreased fetal weight and increased circulating oxLDL/cholesterol levels in WT, but not in LOX-1tg mice. HCD did not alter AngII responsiveness or AT1 expression in both vascular beds; however, AngII responsiveness and AT1 expression were lower in aortas from LOX-1tg compared with WT mice. In aortas from WT-CD mice, acute oxLDL exposure induced AT1-mediated vasoconstriction via LOX-1. HCD impaired endothelium-dependent vasodilation and increased superoxide levels in WT aortas, but not uterine arteries. Moreover, in WT-CD mice oxLDL decreased MCh sensitivity in both vascular beds, partially via LOX-1. In summary, HCD impaired pregnancy outcomes and vascular function, and oxLDL-induced LOX-1 activation may contribute to vascular dysfunction via AT1. Our study suggests that LOX-1 could be a potential target to prevent adverse outcomes associated with vascular dysfunction in preeclampsia.

A High Cholesterol Diet During Late Pregnancy Impairs Long-Term Maternal Vascular Function in Mice

“…We showed that oxLDL further impaired MCh-induced vasodilation in aortas from PP-HCD females only, but not in aortas from PP-CD mice. Interestingly, while we previously demonstrated that oxLDL impairs endothelium-dependent vasodilation in aortas from pregnant mice on a control diet, 17 we did not find oxLDL-induced vascular effects in aortas from postpartum mice on a control diet mice. Thus, it may be speculated that the maternal vasculature from pregnant mice is more susceptible to oxLDL-induced vascular effects compared with nonpregnant vessels.…”

“…After washing with PSS and return to baseline, selected baths were pre-incubated with (1) the pan nitric oxide synthase (NOS) inhibitor N G -nitro-L-arginine methyl ester (L-NAME; 1×10 − 4 mol/L, Sigma-Aldrich) for 30 min to evaluate NO contribution to vasodilation or (2) oxLDL (50 μg/mL; medium oxLDL, Kalen Biomedical, LLC, Germantown, MD) for 10 min to evaluate the vascular responses to atherogenic lipid environment, before the start of the cumulative concentration response curve (CCRC) to MCh. Vessels were then pre-constricted with PE EC 80 (4×10 − 6 mol/L) (calculated from our previous study) 17 for 5 min (or until plateau) followed by the CCRC to MCh (1×10 − 10 to 1×10 − 4 mol/L; MCh doses were added in 2-min intervals). After 4 washes with PSS and a 30-min equilibration period, control baths and baths pre-incubated with oxLDL (10 min prior to start of CCRC), were exposed to a PE CCRC (1×10 − 9 to 1×10 − 3.7 mol/L; PE doses were added in 2-min intervals, or until plateau).…”

“…Vascular dysfunction in complicated pregnancies is associated with increased oxidative stress and systemic inflammation, which decreases the bioavailability of nitric oxide (NO) to vasodilation. 13,14 In addition, increased circulating levels of atherogenic lipids, 15 such as LDL 11 and oxLDL, 16 in pregnancy, are associated with endothelial dysfunction 17 and an increased risk for cardiovascular complications later in life. 18 These data suggest a potential role for these increased atherogenic lipids in the long-term effects of pregnancy complications, but also dyslipidemia in general, on maternal vascular health, which may be associated with the higher risk for CVD in these women.…”

Two Strikes and You Are Out: Long-Term Cardiovascular Consequences of the Additive Effects of Pregnancy and a Brief High-Cholesterol Diet

“…This could be explained by the animal model, since in a prior publication, Saez et al 20 did observe ox-LDL-related endothelial dysfunction in a different mouse strain. 20 Alternatively, failure to observe a shift in sensitivity to methacholine might be explained by use of a single dose of the endothelium-dependent dilator, rather than generating a dose-response curve. Finally, it should be noted that the failure to identify early histological evidence of atherosclerosis may be due to insufficient duration of follow-up, or to the resistance of C57BL/6 mice to atherosclerosis in the absence of persistent and severe hypercholesterolemia as well as a proinflammatory diet.…”

An Overview of Obesity, Cholesterol, and Systemic Inflammation in Preeclampsia

“…Likewise, the lectin-like oxidized low-density-lipoprotein receptor-2 (LOX1) overexpressing mouse is a model of vascular dysfunction as increased LOX1 induces angiotensin activation and leads to PE associated outcomes [ 35 ]. LOX1 has been associated with the development of hypertension, insulin resistance, hyperlipidemia and complications associated with obesity [ 36 ].…”