Project ID CM-HD2026_63

ThemeCM-HD

Co Supervisor 1A Dr Sarah Chapple Faculty of Life Sciences & Medicine, School of Cardiovascular and Metabolic Medicine & Sciences, Vascular themeEmail

Co Supervisor 1B Prof Paul Taylor Faculty of Life Sciences & Medicine, School of Life Course & Population Sciences, Department of Women & Children’s HealthEmail

Exploring the relationship between Nrf2-dependent maternal cardiovascular and glucose handling during pregnancy

Scientific basis:
Gestational diabetes (GDM) affects 5-25% of pregnancies and is defined as new onset diabetes in pregnancy. The aetiology of GDM is multifactorial, but commonly mothers are obese and have markers of pre-existing oxidative stress/inflammation and/or insulin resistance. Nrf2 is a transcription factor which regulates a wide range of inducible antioxidant and phase-II detoxification genes, protecting the body against oxidative stress. In human pregnancy activation of Nrf2 with the neutraceutical sulforaphane reduces maternal blood pressure in hypertensive mothers, and improves fasting blood glucose and HbA1c levels in non-pregnant T2DM patients. Nrf2 has also been shown to play a role in maternal pancreatic adaptation in murine pregnancy, with beta-cell specific deletion of Nrf2 resulting in a GDM like phenotype. Using a model of murine obesity-induced GDM, our lab has shown sulforaphane improves pregnancy outcomes, as well as maternal glucose handling and vascular function, but the relationship between the two is unknown.

Project objective/Techniques/Skills:
The objective is to use GDM control and beta-cell specific Nrf2 knockout mice to test the hypothesis that Nrf2-dependent dysregulation of maternal glucose handling ultimately leads to maternal vascular dysfunction in GDM pregnancy.

Cre-LoxP gene editing will be used to delete Nrf2 from pancreatic beta-cells exacerbating glucose dysregulation during GDM pregnancy, allowing the Nrf2-dependent effects of maternal glucose regulation on cardiovascular function to be assessed. Gold standard/cutting edge surgically implanted telemetric probes will be used to monitor maternal cardiovascular/glucose handling during pregnancy, the latter representing continuous glucose monitoring (CGM) technology being increasingly used to manage human diabetes. Telemetric probes allow continuous, unrestrained recording throughout pregnancy of parameters such as heart rate, blood pressure and blood glucose, producing large physiological data sets. Imaging techniques (e.g. LCSI, photoacoustic imaging), histology and/or myography will be used to further assess in vitro vascular function in specific resistance beds.

Aims/Timeline:
3M rotation: Assessment of Nrf2-dependent beta cell deletion on uterine blood flow using LCSI imaging

Year 1/2: Temporal assessment of Nrf2-dependent cardiovascular function throughout pregnancy using telemetry, myography and imaging of blood flow in resistance beds. Skills: animal husbandry of transgenic lines, genotyping, telemetric surgery and histology of isolated vessels to determine the effect of Nrf2-dependent glucose handling on vascular remodelling

Year 3/4: Temporal monitoring of Nrf2-dependent glucose handling throughout pregnancy using telemetry, to assess parameters such as glucose variability and mean blood glucose. The student will also learn how to conduct glucose tolerance testing assessments

Years1-4:Presentation of findings at lab meetings/conferences

Representative Publications

1. Psefteli PM, Morris JK, Ehler E, Smith L, Bowe J, Mann GE, Taylor PD, Chapple SJ. ‘Sulforaphane induced NRF2 activation in obese pregnancy attenuates developmental redox imbalance and improves early-life cardiovascular function in offspring’ Redox Biol. 2023 67:102883 doi: 10.1016/j.redox.2023.102883.
2. Kennard M, Nandi M, Chapple SJ, King A. ‘The glucose tolerance test in mice: sex, drugs and protocol’ Diabetes Obesity & Metabolism 2022 24(11):2241-2252 doi: 10.1111/dom.14811
3. Cheng X, Chapple SJ, Patel B, Puszyk W, Sugden D, Yin X, Mayr M, Siow RCM, Mann GE. ‘Gestational diabetes mellitus impairs Nrf2-mediated adaptive antioxidant defenses and redox signaling in fetal endothelial cells in utero’ Diabetes 2013 62(12):4088-97 doi: 10.2337/db13-0169

1. Samuelsson, AM, Morris A, Igosheva N, Kirk, S L, Pombo J M, Coen CW, Poston L & Taylor PD. (2010). Evidence for sympathetic origins of hypertension in juvenile offspring of obese rats. Hypertension 55, 76-82 (plus Editorial Comment; Rahmouni, K., Sympathetic tone in the young: the mother weighs in. Hypertension. 55(1): p. 21-2). DOI HYPERTENSIONAHA.109.139402 [pii] 10.1161/HYPERTENSIONAHA.109.139402
2. Maragkoudaki X, Naylor M, Papacleovoulou G, Stolarczyk E, Rees D, Pombo JM, Abu-Hayyeh S, Czajka A, Howard JK, Malik AN, Williamson C, Poston L & Taylor PD. (2020) Supplementation with a prebiotic (polydextrose) in obese mouse pregnancy improves maternal glucose homeostasis and protects against offspring obesity. Int J Obes (02/07/19). DOI: 10.1038/s41366-020-00682-5.
3. Taylor PD, Gu H, Saunders H, Fiori F, Dalrymple KV, Sethupathi P, Miller F, Jones B, Costa Vieira M, Singh C, Briley A, Seed P, Pasupathy D, Santosh P, Groves AM, Sinha MD, Chowienczyk PJ & Poston L on behalf of the UPBEAT Consortium. (2022) Lifestyle intervention in obese pregnancy and cardiac remodelling in 3-year-olds: children of the UPBEAT RCT. Int J Obesity DOI: 10.1038/s41366-022-01210-3.