Title: Investigating novel treatments for maternal vascular dysfunction in the STOX1 model of pre-eclampsia; the missing link in the translational pathway
Funder: The Academy of Medical Sciences

Abstract: In the hypertensive pregnancy disorder pre-eclampsia, the maternal syndrome is driven by small artery dysfunction. Several putative therapeutics for maternal vascular dysfunction, such as kynurenine, have been investigated in vitro and now require testing in a suitable animal model of pre-eclampsia. Aim 1: Locally establish and validate the STOX1 model of PE Objectives: Generate pregnant mice with STOX1 over-expression (‘STOX1’) Compare features of the maternal vascular phenotype, including blood pressure (BP) and ultrasound Doppler indices, between STOX1 and wild-type (WT) pregnant dams. Aim 2: Assess the effects of a novel therapeutic in the STOX1 model of PE Objectives: Administer kynurenine to pregnant STOX1 and WT dams Compare maternal and fetal outcomes in hypertensive and normotensive mice treated with kynurenine or vehicle Female FVB/N mice randomised to mating with WT males (control) or males transgenic for the human STOX1 transcription factor (TgSTOX1; n=4/group) will undergo repeated, blinded assessments of BP, proteinuria and ultrasound Doppler indices throughout gestation and fetoplacental assessment at E18.5 to validate recapitulation of the reported STOX1 phenotype. Subsequently, FVB/N females randomised to WT or TgSTOX1 mating will be randomly allocated to receive kynurenine (100 mg/kg/day) in drinking water from E7.5 or control (n=9/group). Blinded assessments of the effects of kynurenine on maternal BP (primary outcome) and secondary maternal and fetal outcomes will be performed. An animal model suitable for testing the effectiveness and safety of new treatments for pre-eclampsia will be an essential component of my future BHF Intermediate Clinical Fellowship.

Lay abstract: Pre-eclampsia is a pregnancy-specific disease which causes high blood pressure and organ dysfunction. It affects 1 in 20 pregnant women in the UK and is a leading cause for babies to be stillborn or to be born very early. Symptoms of preeclampsia are caused by problems with the mother’s small blood vessels, and new treatments for this are needed urgently. Several potential new treatments have been tested in the laboratory and show beneficial effects in small arteries donated by women with pre-eclampsia. Before testing new treatments in pregnant women, it is essential to test them in pregnant animals to ensure they work and are safe for both mother and baby. Animals do not develop pre-eclampsia so new treatments require testing in animals that have been manipulated to develop symptoms that are similar to human pre-eclampsia. I will obtain a modified mouse strain called ‘STOX1’. STOX1 pregnant females develop high blood pressure, organ dysfunction, small offspring and other features similar to pre-eclampsia. First, I will test that STOX1 mice demonstrate these symptoms by comparing blood pressure, protein in the urine and ultrasound measurements between STOX1 and normal pregnant mice. Next, I will use the STOX1 model to test the effects and safety of a possible new treatment for pre-eclampsia, called kynurenine. Normal pregnant mice and STOX1 pregnant mice will either receive drinking water containing kynurenine or water only. I will measure the effects of treatment on blood pressure and other features of maternal pre-eclampsia, including fetal growth and survival.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH