Contribution of medullary pre-sympathetic neurons on cardiovascular dysfunction during transition to menopause

Schwarz Flores, Karla Gabriele

Contribution of medullary pre-sympathetic neurons on cardiovascular dysfunction during transition to menopause

Date

2025

Authors

Schwarz Flores, Karla Gabriele

Abstract

Cardiovascular disease is a highly prevalent condition in middle-aged women and are among the leading cause of poor patient’s quality of life and is recognized as the woman’s greatest health threat. Importantly, recent evidence suggests the existence of an intimate crosstalk between the heart and the brain, resulting from a complex network of neurohumoral circuits. From a pathophysiological perspective, the higher prevalence of heart disease in elderly women, may be explained in part by sex-related differences in cardiovascular disease’s risk factors. The autonomic nervous system is a major physiological actor affecting heart-brain axis in health and disease. Importantly, accumulating evidence support the negative impact of decreased estrogen due to menopause transition as a risk factor for adverse cardiovascular events, possibly contributing to autonomic imbalance in middle-aged women, however this hypothesis has not been comprehensive tested before. Central autonomic nuclei, such as the rostral ventrolateral medulla (RVLM) encompasses a pivotal circuit of control of sympathetic flow and blood pressure. Overactivity of sympathetic tone is a hallmark of cardiovascular disorders, including hypertension, stroke and HF. In fact, it was suggested that estrogens exert direct effects on RVLM through estrogen receptors (ERα and ERβ), thereby leading to sympathoinhibitory effects, which may be crucial for cardiovascular protection. While a strong causal-association between sympathetic overactivity and development of cardiovascular diseases has been previously established, further interdisciplinary studies are needed to better understand the underlying cellular/molecular and physiological mechanisms, particularly in the perimenopausal and postmenopausal women. If a reduced estrogen signaling through neuronal ERs contributes to aberrant pre-sympathetic neural activity during menopause leads to autonomic imbalance, cardiovascular disorders and exercise capacity remains totally unknown. My underlying hypothesis is that normalizing autonomic nervous function during perimenopause will have a positive impact on cardiac function in experimentally healthy menopause. I proposed an integrative approach by combining freely moving animal recordings, chemogenetic and hormone treatment to assess cardiovascular/autonomic function in a preclinical model of menopause transition using 4-vinylcyclohexane- mediated accelerated ovarian failure. Furthermore, cellular and molecular mechanisms associated with ERs signaling were elucidated using in vitro model of menopause. In this proposal, I determined, for the first time that, i) estrogen decrease during perimenopause triggers brainstem pre-sympathetic neurons (RVLM C1) overactivity WT mice, leading to cardiac autonomic imbalance, arrhythmogenesis and cardiac diastolic and systolic dysfunction; ii) RVLM C1 neurons contribute to cardiac sympathetic overactivity, cardiac arrythmias and cardiac impairment in postmenopausal mice; iii) long-term 17β-estradiol treatment during perimenopause decrease RVLM C1 activity, improving cardiac function in postmenopausal stage. Together, the results suggest that RVLM C1 neurons play a major role in cardiovascular remodeling during female reproductive senescence.

Description

Tesis (Doctorado en Ciencias Biológicas Mención Ciencias Fisiológicas)--Pontificia Universidad Católica de Chile, 2025
TESIS EMBARGADA POR LA ALUMNA HASTA EL 01 DE DICIEMBRE DE 2025