Apolipoprotein A1 mimetic peptide ATI-5261 reverses arterial stiffness at late pregnancy and early postpartum in a COMT-/- mouse model of preeclampsia

Abstract

Background: Preeclampsia (PE) is a serious maternal complication during pregnancy. Associated arterial stiffness in PE patients leads to increased risks of cardiovascular diseases later in life. Cholesterol efflux capacity, especially ATP binding cassette transporter A1 (ABCA1) dependent capacity, has been proposed to be a likely mediator of arterial stiffness. In the present study, we aimed to evaluate the effect of an apolipoprotein A1 mimetic peptide ATI-5261 on arterial stiffness in a mouse model of PE. Methods: Pregnant COMT-/- mice were randomized to receive vehicle or ATI-5261 (30 mg/kg per day) via subcutaneous injection from gestational days (GD) 10.5 to GD 18.5 or to 10 days postpartum. Pregnant C57BL/6 J mice received vehicle during paralleled periods were served as normal controls. Results: COMT-/- mice displayed maternal hypertension and proteinuria during pregnancy. Carotid-femoral pulse wave velocity (PWV) was increased at GD 18.5 and 10 days postpartum. ATI-5261 treatment in COMT-/- mice significantly reduced PWV and partially normalized impaired ex vivo vascular function at late pregnancy and early postpartum. ATI-5261 treatment also increased serum ABCA1 concentrations and cholesterol efflux capacity, as well as ABCA1 expressions in the placenta. Pup weights, crown to rump lengths and abdominal circumferences were reduced in COMT-/- mice. Treatment with ATI-5261 did not alter these fetal measurements but significantly reduced placental weights and increased fetal to placental ratios in COMT-/- mice. Conclusion: ATI-5261 reversed arterial stiffness at late pregnancy and early postpartum in a COMT-/- mouse model of PE and may be a potential therapy for arterial stiffness associated with PE.