The effect of activating AVP-producing neurons during pregnancy on the development of preeclampsia in female mice

• Grant number: 24/00784-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: October 01, 2024
• End date: September 30, 2026
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Andre de Souza Mecawi
• Grantee: Ana Beatriz Henrique dos Santos
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated research grant: 19/27581-0 - Control of vasopressin secretion in pregnancy and its implications in pathophysiology of Preeclampsia, AP.JP

Abstract

Pregnancy is a period of extreme physiological changes in females, adapting the mother's body to ensure the healthy development of the embryo/fetus. Preeclampsia (PE) is a pregnancy-related disease characterized by the development of hypertension in the second half of gestation, associated with proteinuria and/or dysfunction of target organs. It affects 3 to 5% of pregnant women worldwide and 8% in the poorer regions of Brazil, being a major cause of maternal-fetal mortality. It has long been known that there is a reduction in the osmotic threshold for the activation of vasopressin-producing neurons (AVP) during pregnancy, but only in this decade has the hypersecretion of this vasoactive hormone been implicated in the induction of PE. Despite this recent finding, the mechanisms responsible for the increased secretion of AVP and the consequent induction of PE are not known. Additionally, there is no literature confirming that chronic hyperactivation of magnocellular neurons producing AVP in the hypothalamus throughout pregnancy is capable of inducing the preeclamptic phenotype. This project aims to assess the role of increased activity of AVP-producing neurons during pregnancy in the development of signs and symptoms of preeclampsia in female mice. Using Cre-loxP technology to produce animals expressing the stimulatory Designed Receptors Exclusively Activated by Designed Drugs (DREADD) in AVP-producing neurons, we intend to understand whether increased activity of AVP-producing neurons can induce PE in mice. Preliminary data from our research group showed an average transfection rate of 73% of AVP neurons in the supraoptic nucleus of female AVP-Cre mice with an adenoviral vector carrying the sequence for expressing the stimulatory DREADD. We also demonstrated intense specific activation of AVP-producing MNC neurons after administration of clozapine N-oxide (CNO) in drinking water for 3 days, observing clear marking of the c-FOS protein in the nucleus of these neurons. Thus, with this approach, we hope to contribute to the understanding of the role of MCNs and the hypersecretion of AVP during pregnancy in the induction of PE.