Neuroendocrine basis of arterial hypertension: involvement of the adrenal medullary tissue (projet "Surr-Tension")

We propose to investigate the neuroendocrine basis of arterial hypertension, which represents the most frequently encountered pathology in response to chronic exposure to a stressful environment. This proposal brings together three teams engaged in the study of cellular and tissular mechanisms involved in vascular pathologies and associated mitochondrial dysfunction correlated with risk factors (stress, aging, diabetes,…). Our organism is daily subjected to environmental changes often perceived as stressors and copes with this by triggering physiological adaptive responses, mediated in particular by an increase in circulating catecholamines. Catecholamines are among the first mediators to be released in response to stress and the adrenal medulla, which is the main source of circulating epinephrine, plays a crucial role in this process. Once delivered into the blood circulation, catecholamines exert multiple actions in particular on the cardiovascular system, leading to appropriate adjustments of blood pressure and cardiac rhythm, and on the energy metabolism. However, as a consequence of prolonged or repetitive stress, adaptive mechanisms can dysregulate, contributing to the development of several illnesses including vascular pathologies such as arterial hypertension or atherosclerosis. Although it is clearly accepted that increased circulating catecholamines can contribute to such pathologies, the involvement of the adrenal medullary tissue in arterial hypertension remains largely neglected. The SURR-TENSION project proposes to address this issue by characterizing the anatomo-functional changes occurring in the adrenal medullary tissue of a strain of spontaneously hypertensive rats. The study will be conducted using two complementary investigation approaches, both at the functional level (ex vivo in acute adrenal slices and in macrodissected medulla and in vivo in anaesthetized and freely moving rats) and at the transcriptional level. We will first focus on the remodeling of the major cellular/intercellular pathways involved in stimulus-secretion coupling, i) chromaffin cell excitability, which ensures the direct control of catecholamine secretion, ii) cholinergic synaptic transmission via the splanchnic nerve terminals that control chromaffin cells excitability and iii) gap junction-mediated cell-cell coupling allowing direct electrical and metabolic communication between chromaffin cells. Second, we will address the role of mitochondria, a Ca2+- sequestering organelle that plays an important role in cytosolic Ca2+ homeostasis and therefore in catecholamine secretion. Indeed, emergent studies argue for a role of mitochondria in the dysregulation of adrenal stimulus-secretion coupling occurring in hypertension. Mitochondria will be investigated both for their ability to regulate intracellular Ca2+ homeostasis and for their crucial contribution to cellular bioenergetics (ATP production, activity of mitochondrial enzymes, mitochondrial membrane potential). This project dealing with "Stress" and "Health" will contribute to identify new adrenal medullary targets that could potentially be pertinent for the prevention or treatment of stressassociated pathologies. The SURR-TENSION project is clearly interdisciplinary and involves a unique combination of various technical and scientific expertise, brought by the three partners. The results will have direct scientific, economic and societal impacts since they will i) prompt further research on the link between the adrenal medullary tissue and the development and/or maintenance of arterial hypertension, ii) allow to formulate new recommandations for stress care, and iii) provide new molecular or cellular targets for preclinical and clinical R&D in stress-associated disorders