Biology subjects

Faedda, N.

Publications and source records attributed to Faedda, N..

3 recordsLinked to original sources

bioRxiv2025

Sexually dimorphic interzonal crosstalk reshapes the adrenal cortex in response to pathophysiological challenges

Structured Abstract BackgroundPrimary aldosteronism is the most common form of secondary arterial hypertension, due to autonomous aldosterone production from the adrenal cortex. Genome wide association studies discovered genetic risk loci associated with the disease, which may affect adrenal cortex renewal, differentiation and lineage conversion. Genetic susceptibility may be modulated by environmental challenges. MethodHere we investigate how environmental cues affecting mineralocorticoid output modulate adrenal cortex homeostasis, cell lineage conversion and zone-specific transcriptional landscape. We have used a newly developed Cyp11b2Cremouse model and characterised its adaptation to a high or low salt diet (HSD, LSD), as well as dexamethasone (DEX) treatment. To explore underlying mechanisms, deep functional and morphological phenotyping, lineage tracing and spatial transcriptomics of the adrenal cortex were performed. ResultsCyp11b2 expression was detected in Cyp11b2Cre-mTmG mice as early as day P1 in different areas of the ZG, associated with high plasma aldosterone levels, with lineage conversion of zona glomerulosa (ZG) into zona fasciculata (ZF) cells progressing between 2 and 9 weeks of age and a progressive reduction of ZG size and evolution of cell components of the adrenal cortex over time. Transdifferentiation progressed into the X-zone (ZX) in females, revealing a previously unrecognized connection between ZF and ZX cells in adult mice. A sexually dimorphic, reciprocal interaction between the ZG and the ZF in adapting to salt diets or DEX treatment was observed, involving changes in cell composition and transcriptional reprogramming of the three zones. ConclusionHSD, LSD and DEX induce a sexually dimorphic cellular and transcriptional response, involving all layers of the adrenal cortex, and the reciprocal contribution of ZG and ZF cells, indicating functional interaction between adrenocortical zones in adapting to external cues.

physiology↗

bioRxiv2025

Blood-borne sphingosine 1-phosphate maintains vascular resistance and cardiac function.

G protein-coupled receptors (GPCRs) are key regulators of cardiovascular function that provide targets for the treatment of cardiovascular disease. Sphingosine 1-phosphate (S1P) is an erythrocyte- and platelet-derived lipid mediator with cognate GPCRs on endothelial cells (EC), vascular smooth muscle cells (VSMC) and cardiomyocytes. S1P circulates in plasma bound to apolipoprotein M (ApoM)-containing high-density lipoproteins (HDL) and to albumin. Circulating S1P levels correlate positively with systolic blood pressure in hypertension and negatively with severity in septic shock and with left ventricular (LV) function in coronary heart disease. In mice, impaired S1P binding to HDL or signaling to EC both trigger hypertension, supporting an essential role for HDL-S1P in supporting endothelial function. The roles of albumin-S1P and myocyte S1PRs in cardiovascular homeostasis remain incompletely defined. Contrasting isolated HDL-S1P deficiency, we report that non-selective depletion of circulating S1P pools in mice impairs LV contractile function and induces hypotension and resistance to the spontaneous increase in blood pressure with age. Cardiac output was preserved in naive S1P deficient mice by compensatory LV dilation, but cardiac reserve reduced in a dobutamine stress test. These phenotypes tracked with hematopoietic cell S1P production and were partially or fully reversed by erythrocyte transfusion. Hypotension was accompanied by reduced peripheral resistance, and S1P infusion dose-dependently increased vascular resistance in isolated perfused kidneys from wild-type mice but not mice with compound deficiency in S1PR2&3. Epistatic analysis supported a critical role for S1PR3 in S1P-dependent blood pressure regulation and pointed to a distinct origin of the cardiac phenotype. Although circulating S1P is elevated in hypertensive mice and humans, increasing circulating S1P was not sufficient to induce hypertension in naive mice. These observations suggests that albumin-S1P crosses the endothelium in resistance arteries to gain access to contractile VSMC S1P receptors, and that myocyte S1PR signaling is essential for vascular resistance and blood pressure maintenance in mice. They also highlight the role for plasma chaperones in specifying vascular responses to S1P and the relevance of S1P as a biomarker and potential therapeutic target for blood pressure regulation and heart failure.

physiology↗

bioRxiv2024

Modulation of calcium signaling on demand to decipher the molecular mechanisms of primary aldosteronism

Primary aldosteronism (PA) is the most common form of secondary hypertension. Major advances have been made in our understanding of PA with the identification of germline and somatic mutations in ion pumps and channels. These mutations lead to the activation of calcium signalling, the major trigger of aldosterone biosynthesis. To elucidate the molecular mechanisms underlying the development of PA, we established an adrenocortical cell model in which we can modulate sodium entry into the cells "on demand" leading to calcium signalling activation. These cells recapitulated the major features of KCNJ5 mutations, the most frequent genetic alteration identified in Aldosterone-Producing-Adenoma. Activation of calcium signalling was associated with increased aldosterone biosynthesis and decreased cell proliferation. RNA sequencing and steroidome analyses revealed unique profiles associated with Na+ entry. Altogether, this work offers valuable insights into the role of sodium-induced calcium signalling in PA development and paves the way for developing new therapeutic strategies.

physiology↗