GLP-1receptor agonists effects on the placenta and maternal vasculature in an obese pregnancy model
Primary Supervisor: Prof. Susan Ozanne (seo10@cam.ac.uk)
Secondary: Prof. Wei Li (wl225@medschl.cam.ac.uk)
Host Department or Institute: Institute of Metabolic Science Metabolic Research Laboratories
Project description
Over 50% of women enter pregnancy overweight or living with obesity. Obesity is associated with an increased risk of pulmonary hypertension, potentially through mechanisms involving endothelial dysfunction, inflammation and cardiometabolic alterations1. An obese pregnancy is associated with adverse cardiovascular adaptations, poor placental function and may increase susceptibility to pulmonary vascular dysfunction2. Maternal vascular adaptation is essential for adequate uteroplacental perfusion and normal placental function. Conversely, placental-derived vasoactive and angiogenic factors modulate maternal vascular homeostasis. Disruption of this bidirectional relationship may contribute to pregnancy complications and adverse fetal outcomes3.
Drugs such as semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro), which mimic incretin action have revolutionised treatment of obesity in non-pregnant individuals. Over 1.6 million people in the UK are taking these drugs which lead to substantial weight loss and improvements in insulin sensitivity and blood pressure in people living with obesity and type 2 diabetes4. Although not recommended, there are an increasing number of pregnancies in individuals taking incretin receptor agonists, likely resulting from increased fertility associated with weight loss and the reduced effectiveness of oral contraceptives whilst taking these agents. However, the impact of periconceptional exposure on maternal and offspring health is poorly understood5. Use of incretin receptor agonists in women of reproductive age is increasing rapidly so the number of exposed pregnancies will continue to increase. There is thus an urgent need for more research to address the knowledge gaps in this area. A randomised control trial of GLP-1RA in human pregnancy is not possible (agents not licenced for use in pregnancy). Therefore, these studies can only be performed in pre-clinical models. The aims of this project are
Aim 1: To compare pregnancy uterine blood flow and placenta blood flow in obese mice treated with an incretin agonist vs. untreated obese mice
Aim 2: To compare indices of cardiovascular function in obese mice treated with an incretin agonist vs. untreated obese mice (i) pre-pregnancy, (ii) during pregnancy and (iii) after weaning.
Aim 3: Profile the microRNA content of placenta-derived EVs from obese treated vs untreated mice to explore this as a potential mechanism for communication between maternal vasculature and the placenta.
This project will therefore investigate the effects of incretin treatment on perigestational maternal vascular and placenta function and communication via microRNAs.
Candidate background
- Interest in or willingness to perform experiments in mice.
- At least a basic understanding and some practical laboratory experience in pipetting/liquid handling, nucleic acid and/or protein gel electrophoresis, working out concentrations and dilutions and dosing
References
- Friedman SE, Andrus BW. Obesity and pulmonary hypertension: a review of pathophysiologic mechanisms. J Obes. 2012; 2012:505274. PMID: 22988490
- Patel D, Avesani M, Johnson MR, Di Salvo G, Savvidou MD. Maternal cardiovascular adaptation to pregnancy in obese pregnant women. Acta Obstet Gynecol Scand. 2024 May;103(5):907-916. doi: 10.1111/aogs.14777. Epub 2024 Jan 18. PMID: 38238936
- Thornburg KL, Louey S. Uteroplacental circulation and fetal vascular function and development. Curr Vasc Pharmacol. 2013 11(5):748-57. PMID: 24063386
- Drucker DJ. The expanding landscape of GLP-1 medicines. Nat Med. 2026;32(1):47-57. PMID: 41482564
- Dearden L, Ozanne SE. Incretin receptor agonism during pregnancy: implications for mother and baby. Clin Sci (Lond). 2025;139(23):1597-1610. PMID: 41359794