Vascular and hormonal interactions in primary aldosteronism

Abstract

Primary aldosteronism (PA) is the most frequent form of secondary hypertension. We hypothesize that adrenal vascular changes may modify adrenal cortex structure and function leading to increased nodulation, creating a propitious environment for the occurrence of somatic mutations and development of aldosterone producing adenoma (APA). The overall aim of this study was to understand the interactions between the vasculature and cell proliferation in particular in the phenomena of zonation of the adrenal cortex and aldosterone production, by using a new generated mice model. A new mouse models was generated, expressing the Cre recombinase under the control of the Cyp11b2 promoter and driving its expression specifically in the aldosterone-producing adrenal zona glomerulosa (ZG); those mice were crossed with mTmG reporter mice (Cyp11b2-Cre::mTmG). Mice adrenal structure and vascularization were characterized under basal conditions and following high/low salt diets as well as dexamethasone treatment to challenge adrenocortical remodeling and function. In Cyp11b2-Cre::mTmG mice, expression of the Cre recombinase was restricted to the zona glomerulosa (ZG), its expression being absent in other tissues. While at day 1, only a few GFP+ cells were present in the ZG, at day 14 all cells of the ZG were GFP+. Subsequently, GFP+ cells transdifferentiate and colonize the zona fasciculata (ZF); this migration is faster in females than in males. Under high salt diet, Cyp11b2 expression was reduced, whereas under low salt diet, the ZG was expanded and Cyp11b2 expression increased. After 2 weeks of dexamethasone treatment, complete disorganization of the ZF was observed; podocalyxin staining showed concomitant disorganization of centripetal capillaries between columns of fasciculata cells. Three weeks after end of treatment, ZF and vessel regeneration was complete in both female and male mice. Experiments are currently ongoing to investigate how modifications of adrenal vascularization may affect adrenal structure and function. This model allows us to evaluate the hormonal influence on the steroidogenic cell lineage and on the adrenal vascular network and will provide new insight in the mechanisms of APA development.