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

Abstract

Acute hyperglycemia (HG) plays a key role in the development of arterial complications and upregulation of Piezo1. Piezo1 appears to mediate shear stress-induced activation of cytosolic endothelial nitric oxide synthase (NO), through incompletely elucidated pathways. Here, we hypothesize that Piezo1 contributesto the organ-specific detrimental effects of HG on arterial myocytes vasoreactivity and excitability by activating NO signaling. We integrated our in silico model of Piezo1channel into a model of rat arterial myocytes and introduced Piezo1-NO signaling consistent with in vitro data. We explored the influence of individual ioniccurrents and transporters on global cytosolic [Ca2+]I (Cai) and membrane potential (Em) in a sensitivity analysis on 1000 virtual cells. Our results suggest theintensified contribution of L-type Ca2+ channel (LTCC) on Cai in HG. Similarly, the impact of large conductance Ca2+ -activated K+ channel (BKCa) on Em and Caiincreased in HG, in accord with reported BKCa channel activity and sensitivity to Ca2+ in vitro. Remarkably, Piezo1 perturbations instigated opposing effects on Emand 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.