Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Relaxin reduces responses to angiotensin II in pregnancy and reverses vascular dysfunction in mouse and human arteries (#200)

Sarah A Marshall 1 , Sevvandi N Senadheera 1 , Kelly O'Sullivan 1 , Marianne Tare 2 , Natalie J Hannan 3 , Jane E Girling 4 , Chen Huei Leo 1 , Laura J Parry 1
  1. School of BioSciences, University of Melbourne, Parkville, Victoria, Australia
  2. Department of Physiology and School of Rural Health, Monash University, Clayton, Victoria, Australia
  3. The Translational Obstetrics Group, Mercy Hospital for Women, Department of Obstetrics and Gynaecology, University of Melbourne, Heidelberg, Victoria, Australia
  4. Gynaecology Research Centre, Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia

Preeclampsia (PE) affects between 3-8% of all pregnancies worldwide and is a leading cause of maternal and fetal death. One characteristic of PE is widespread maternal vascular dysfunction. The peptide hormone relaxin (RLX) reduces all-cause mortality in acute heart failure patients through its vasodilatory effects on the systemic vasculature. In this study, we tested the hypothesis that RLX treatment would alleviate symptoms of PE by improving vascular function. Our specific aims were to i) induce vascular dysfunction in human omental and mouse mesenteric arteries ex vivo, and ii) use pregnant RLX-deficient (Rln-/-) mice with enhanced responses to angiotensin II (AngII) to investigate the potential for RLX as a treatment in PE. The ex vivo study used omental arteries from normotensive women having elective caesarean section at term and mesenteric arteries from non-pregnant mice. Arteries were incubated for 3h at 4°C and 24h at 37°C respectively in normal media (DMEM) with conditioned media (exposed to placental explants for 24 hours: PEM, exposed to trophoblast cells: TCM) with soluble Flt-1 levels >1ng/ml, in the presence or absence of 10-30nM RLX (n=5-7/treatment). In the in vivo study, pregnant Rln-/- mice received 0.5ug/h RLX (n=7) or placebo (n=7) subcutaneously via osmotic minipump for 5 days from GD12.5. PEM and TCM induced vascular dysfunction in human and mouse arteries respectively, which was reversed by RLX treatment. RLX treatment in vivo significantly reduced contraction of the mesenteric artery to AngII in Rln-/- mice on GD17.5; these effects were endothelium-independent and likely involve vascular smooth muscle prostanoids. In conclusion, RLX treatment of arteries ex vivo and pregnant Rln-/- mice in vivo reverses endothelial dysfunction. One mechanism of relaxin action is to reduce vascular sensitivity to AngII. These data suggest that RLX could be an effective therapeutic to alleviate maternal systemic vascular dysfunction in pregnant women with PE.