Piezo1-Nitric Oxide Signaling in a Population-based Model of Arterial Myocytes in Acute Hyperglycemia

Acute hyperglycemia (HG) plays a key role in the development of arterial complications and upregulation of Piezo1.Piezo1 appears to mediate shear stressinduced activation of cytosolic endothelial nitric oxide synthase (NO), through incompletely elucidated pathways.Here, we hypothesize that Piezo1 contributes to the organ-specific detrimental effects of HG on arterial myocytes vasoreactivity and excitability by activating NO signaling.We integrated our in silico model of Piezo1 channel into a model of rat arterial myocytes and introduced Piezo1-NO signaling consistent with in vitro data.We explored the influence of individual ionic currents and transporters on global cytosolic [Ca 2+ ]i (Cai) and membrane potential (Em) in a sensitivity analysis on 1000 virtual cells.Our results suggest the intensified contribution of L-type Ca 2+ channel (LTCC) on Cai in HG.Similarly, the impact of large conductance Ca 2+ -activated K + channel (BKCa) on Em and Cai increased in HG, in accord with reported BKCa channel activity and sensitivity to Ca 2+ in vitro.Remarkably, Piezo1 perturbations instigated opposing effects on Em and Cai in control vs. HG-induced conditions, implying a possible role of Piezo1-NO signaling in the heterogeneity of organ-specific vasoactive response to HG in arterial myocytes and thus a promising therapeutic avenue.