Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure

0585336 - FGÚ 2025 RIV CH eng J - Journal Article
Kolesová, Hana - Hrabalová, Petra - Bohuslavová, Romana - Abaffy, Pavel - Fabriciová, Valeria - Sedmera, David - Pavlínková, Gabriela
Reprogramming of the developing heart by Hif1a-deficient sympathetic system and maternal diabetes exposure.
Frontiers in Endocrinology. Roč. 15, Mar 5 (2024), č. článku 1344074. ISSN 1664-2392. E-ISSN 1664-2392
R&D Projects: GA ČR(CZ) GA21-03847S; GA MŠMT(CZ) LX22NPO5104; GA MŠMT(CZ) EF18_046/0016045
Research Infrastructure: Czech-BioImaging II - 90129; CCP II - 90126
Institutional support: RVO:67985823 ; RVO:86652036
Keywords : mouse model * maternal diabetes * coronary arteries * sympathetic neurons * cardiac sympathetic system
OECD category: Cardiac and Cardiovascular systems; Endocrinology and metabolism (including diabetes, hormones) (BTO-N)
Impact factor: 5.2, year: 2022
Method of publishing: Open access
https://doi.org/10.3389/fendo.2024.1344074

Introduction: Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence the offspring's cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affects the development of the cardiac sympathetic system and, consequently, heightens health risks and predisposes to cardiovascular disease remain poorly understood.Methods and results: In the mouse model, we performed a comprehensive analysis of the combined impact of a Hif1a-deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and Hif1a deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of the adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, and dilated subepicardial veins and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA sequencing (RNA-seq) revealed significant transcriptome changes in Hif1a-deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population.Discussion: Our data demonstrate that a failure to adequately activate the HIF-1 alpha regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus increasing the risk of neonatal death.
Permanent Link: https://hdl.handle.net/11104/0353052