Control of vasopressin secretion in pregnancy and its implications in pathophysiology of Preeclampsia

• Grant number: 19/27581-0
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: June 01, 2021
• End date: May 31, 2026
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Andre de Souza Mecawi
• Grantee: Andre de Souza Mecawi
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Anne Caroline Silva Barbosa ; Camila Nascimento Mantelli ; Charles William Bourque ; David Murphy ; João Victor Silva Nani ; Nelson Sass ; Silvia Daher ; Verónica Trujillo
• Associated research grant(s): 24/19300-9 - Shining light on the functions of a brain non-visual opsin, AP.R SPRINT; 24/01620-7 - Role of hypothalamic magnocellular neurons in mediating the psychedelic and antidepressant properties of ketamine, AP.R
• Associated scholarship(s): 25/04731-7 - Multiomic analysis (RNAseq and ATACseq) of single cell nuclei from the hypothalamus of mice with preeclampsia, BP.TT; 25/00240-9 - Control of Vasopressin Secretion in Pregnancy and its Implications in Pathophysiology of Preeclampsia, BP.TT; 24/09501-7 - Electrophysiologic and Molecular impacts of three preeclampsia pre-clinic models on vasopressin-producing magnocellular neurons, BP.PD; + associated scholarships 24/00784-6 - The effect of activating AVP-producing neurons during pregnancy on the development of preeclampsia in female mice, BP.MS; 24/16047-0 - Control of Vasopressin Secretion in Pregnancy and its Implications in Pathophysiology of Preeclampsia, BP.TT; 24/01716-4 - Human placental single-cell transcriptomic atlas in physiological and pathological condition, BP.IC; 24/02874-2 - Control of Vasopressin Secretion in Pregnancy and its Implications in Pathophysiology of Preeclampsia, BP.TT; 24/00321-6 - Multiomic analysis (RNAseq and ATACseq) of single cell nuclei from the hypothalamus of mice with preeclampsia, BP.TT; 23/05526-2 - Multiomic analysis (RNAseq and ATACseq) of single cell nuclei from the hypothalamus of mice with preeclampsia, BP.TT; 23/07405-8 - Collection and analysis of physiological, clinical, biochemical, endocrine and genetic data in control and pre-eclamptic pregnant women, BP.TT; 22/12825-3 - Control of vasopressin secretion during pregnancy and its implications for the pathophysiology of preeclampsia, BP.TT; 22/07286-6 - Evaluation of the impact of preeclampsia induced by NOS inhibition on AVP-producing neurons in pregnant mice, BP.IC; 22/04021-1 - Role of vasopressin-producing magnocellular neurons in the development of Preeclampsia in mice, BP.IC; 22/04362-3 - Control of Vasopressin Secretion in Pregnancy and its Implications in Pathophysiology of Preeclampsia, BP.TT; 21/14426-6 - Multiomic analysis (RNAseq and ATACseq) in single-cell nuclei of the hypothalamus of normal mice and during pre-eclamptic gestation, BP.DD; 21/12098-1 - Control of vasopressin secretion in pregnancy and its implications in pathophysiology of Preeclampsia, BP.TT - associated scholarships

Abstract

Pregnancy is a period of extreme changes in the female's physiology, adapting the mother's organism to ensure healthy development of the embryo/fetus. Preeclampsia (PE) is a disease characteristic of pregnancy and is defined by the development of hypertension in the second half of pregnancy, associated with proteinuria and/or target organ dysfunction. It affects between 3 and 5% of pregnant women worldwide and 8% in the poorest regions of Brazil, being the leading cause of maternal and fetal death. It has long been known that there is a reduction in the osmotic threshold for Activation Of Vasopressin (AVP) neurons during pregnancy, but only in this decade the hypersecretion of this vasoactive hormone has been implicated in PE induction. Despite this recent finding, the mechanisms responsible for increased AVP secretion and consequent PE induction are not known. This project aims to study the mechanisms responsible for altering the osmosensitivity of AVP producing neurons in pregnancy, as well as to understand the consequences of their hypersecretion for the development of PE. Using the pre-clinical model of L-NAME-induced pre-eclampsia, we will study the molecular and functional changes of the AVP-producing magnocellular neurons in normal and preeclamptic pregnancy. By using Cre-loxP technology to produce animals that express stimulatory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) on AVP-producing neurons, we intend to understand whether the increased activity of AVP-producing neurons is capable of inducing PE. Due to the importance of estrogen receptors ² (ER²) in the excitability of AVP-producing neurons, we intend to demonstrate the mechanisms by which this receptor may act to increase AVP secretion during pregnancy. By Cre-loxP technology we will perform conditional deletion of ER² in AVP-producing neurons, allowing us to evaluate its implication in the process of synthesis-excitation-secretion coupling of AVP during pregnancy. We do also intend to apply the RNA sequencing technique to discover new genes that may regulate exacerbated AVP secretion during pregnancy and are possibly implicated in the development of Preeclampsia. Finally, we will evaluate the correlation of plasma estrogen and AVP levels with risk and diagnostic factors for the development of Preeclampsia in pregnant women. We expect to contribute to the understanding of changes in the secretion of AVP during pregnancy and its implication in the induction of PE, enabling the development of new strategies for prevention, diagnosis and treatment of this disease. (AU)

Scientific publications

(9)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

R.C. DOS-SANTOS; T. VILHENA-FRANCO; L.C. REIS; L.L.K. ELIAS; J. ANTUNES-RODRIGUES; A.S. MECAWI. AMPA and angiotensin type 1 receptors are necessary for hemorrhage-induced vasopressin secretion. Brazilian Journal of Medical and Biological Research, v. 55, 2022-02-04. (19/01260-2, 19/27581-0)

ELSAMAD, GHADIR; MECAWI, ANDRE SOUZA; PAUZA, AUDRYS G.; GILLARD, BENJAMIN; PATERSON, ALEX; DUQUE, VICTOR J.; SARENAC, OLIVERA; ZIGON, NINA JAPUNDZIC; GREENWOOD, MINGKWAN; GREENWOOD, MICHAEL P.; et al. Ageing restructures the transcriptome of the hypothalamic supraoptic nucleus and alters the response to dehydration. NPJ AGING, v. 9, n. 1, p. 15-pg., 2023-06-01. (19/27581-0)

FELINTRO, VIVIANE; TRUJILLO, VERONICA; DOS-SANTOS, RAONI C.; DA SILVA-ALMEIDA, CLAUDIO; REIS, LUIS C.; ROCHA, FABIO F.; MECAWI, ANDRE S.. Water deprivation induces hypoactivity in rats independently of oxytocin receptor signaling at the central amygdala. FRONTIERS IN ENDOCRINOLOGY, v. 14, p. 12-pg., 2023-01-31. (19/27581-0)

MECAWI, ANDRE SOUZA; VARANDA, WAMBERTO ANTONIO; DA SILVA, MELINA PIRES. Osmoregulation and the Hypothalamic Supraoptic Nucleus: From Genes to Functions. FRONTIERS IN PHYSIOLOGY, v. 13, p. 20-pg., 2022-05-24. (18/07027-5, 19/27581-0, 19/26034-5)

FERNANDEZ, GIMENA; DE FRANCESCO, PABLO N.; CORNEJO, MARIA P.; CABRAL, AGUSTINA; AGUGGIA, JULIETA P.; DUQUE, VICTOR J.; SAYAR, NILUFER; CANTEL, SONIA; BURGOS, JUAN, I; FEHRENTZ, JEAN-ALAIN; et al. Ghrelin Action in the PVH of Male Mice: Accessibility, Neuronal Targets, and CRH Neurons Activation. Endocrinology, v. 164, n. 11, p. 15-pg., 2023-09-23. (16/17968-6, 19/27581-0)

RORATO, RODRIGO; FERREIRA, NATHALIA L.; OLIVEIRA, FRANCIANE P.; FIDELES, HIGOR J.; CAMILO, TAYS A.; ANTUNES-RODRIGUES, JOSE; MECAWI, ANDRE S.; ELIAS, LUCILA L. K.. Prolonged Activation of Brain CB2 Signaling Modulates Hypothalamic Microgliosis and Astrogliosis in High Fat Diet-Fed Mice. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 10, p. 15-pg., 2022-05-01. (16/17968-6, 19/27581-0, 20/11612-0, 14/20704-5, 18/18071-5)

ALVES FERNANDES, ALAN CARLOS; DE OLIVEIRA, FRANCIANE PEREIRA; FERNANDEZ, GIMENA; VIEIRA, LUANE DA GUIA; ROSA, CRISTIANE GUGELMIN; DO NASCIMENTO, TAIS; FRANCA, SUZELEI DE CASTRO; DONATO JR, JOSE; VELLA, KRISTEN R.; ANTUNES-RODRIGUES, JOSE; et al. Arcuate AgRP, but not POMC neurons, modulate paraventricular CRF synthesis and release in response to fasting. CELL AND BIOSCIENCE, v. 12, n. 1, p. 14-pg., 2022-07-28. (16/17968-6, 19/27581-0)

LIN, PANJIAO; GILLARD, BENJAMIN T.; PAUZA, AUDRYS G.; IRAIZOZ, FERNANDO A.; ALI, MAHMOUD A.; MECAWI, ANDRE S.; ALIM, FATMA Z. DJAZOULI; ROMANOVA, ELENA, V; BURGER, PAMELA A.; GREENWOOD, MICHAEL P.; et al. Transcriptomic plasticity of the hypothalamic osmoregulatory control centre of the Arabian dromedary camel. COMMUNICATIONS BIOLOGY, v. 5, n. 1, p. 15-pg., 2022-09-23. (19/27581-0)

DA CRUZ-FILHO, JOAO; COSTA, DANIELY MESSIAS; SANTOS, TATIANE OLIVEIRA; DA SILVA, RAQUEL PRADO; ANJOS-SANTOS, HEVELY CATHARINE; MARCIANO, NAIMA JAMILE DOS SANTOS; RODRIGUEZ-GUZMAN, ROGER; HENRIQUE-SANTOS, ANA BEATRIZ; MELO, JOAO EDUARDO CONCEICAO; BADAUE-PASSOS JR, DANIEL; et al. Water deprivation induces a systemic procatabolic state that differentially affects oxidative and glycolytic skeletal muscles in male mice. AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, v. 328, n. 1, p. 13-pg., 2025-01-28. (19/27581-0)