1. High-cholesterol diet during pregnancy induces maternal vascular dysfunction in mice: potential role for oxidized LDL-induced LOX-1 and AT1 receptor activation
- Author
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Tatsuya Sawamura, Sandra T. Davidge, Raven Kirschenman, Tamara Sáez, and Floor Spaans
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Mice, Transgenic ,Vasodilation ,030204 cardiovascular system & hematology ,Receptor, Angiotensin, Type 1 ,Choline ,Preeclampsia ,Cholesterol, Dietary ,03 medical and health sciences ,chemistry.chemical_compound ,Fetus ,0302 clinical medicine ,Pregnancy ,Superoxides ,Internal medicine ,medicine ,Animals ,Vascular Diseases ,Receptor ,Aorta ,Angiotensin II receptor type 1 ,Cholesterol ,Superoxide ,business.industry ,Angiotensin II ,Body Weight ,General Medicine ,Scavenger Receptors, Class E ,medicine.disease ,Lipoproteins, LDL ,Oxidative Stress ,Uterine Artery ,030104 developmental biology ,Endocrinology ,chemistry ,Vasoconstriction ,cardiovascular system ,Female ,lipids (amino acids, peptides, and proteins) ,Endothelium, Vascular ,medicine.symptom ,business ,hormones, hormone substitutes, and hormone antagonists - 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.
- Published
- 2020