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Molecular regulators of catecholamine response in human pulmonary microvascular endothelial cells

Adrian Lopez Garcia de Lomana, Arnar Ingi Vilhjálmsson, John Denver Rafael Florentino, Eva Jacobsen, Sarah McGarrity, Pär Ingemar Johansson, Óttar Rolfsson

Endothelial dysfunction (ED) is a systemic disease state of endothelial cells (ECs) occurring in a broad variety of pathologies. Sustained high levels of catecholamines associate with endothelial dysfunction and vascular permeability. Indeed, circulating adrenaline levels predict mortality in trauma patients. Yet, the molecular mechanisms that drive ECs into a pathological state in trauma patients upon elevated catecholamine levels are not well characterized.
Here, we identified the transcriptomic, metabolic and lipidomic responses to high levels of catecholamines in human pulmonary microvascular endothelial cells (HPMECs). We treated HPMECs with either separate adrenaline or noradrenaline and together to mimic in vivo conditions. We sampled cultures for molecular profiling at 4 hours after exposure. We identified a total set of 308 differentially expressed genes upon catecholamine exposure across all conditions. In particular, we found GRAMD1B, AREG, PDK4 and CXCR4 as the strongest transcriptional responders to treatment. Functional enrichment of responding genes distribute across three major axes: signalling, metabolism and proliferation/differentiation. Furthermore, we carried out lipidome quantification of cell cultures under conditions of interest. Finally, we plan to integrate transcriptome and lipidome profiles by constraining genome-scale metabolic models to predict differential metabolic fluxes under distinct conditions.
Overall, this integrative analysis collectively builds a whole-scale picture of how signalling pathways downstream catecholamines receptors in ECs trigger a transcriptional state transition that consequently results in metabolic changes that drive ECs out of homeostasis. A precise understanding and prediction of ECs molecular states are fundamental to the discovery of more efficient clinical interventions in trauma patients.


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