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Resistance arteries and arterioles evolved as specialized blood vessels serving two important functions: (a) regulating peripheral vascular resistance and blood pressure and (b) matching oxygen and nutrient delivery to metabolic demands of organs. These functions require control of vessel lumen cross-sectional area (vascular tone) via coordinated vascular cell responses governed by precise spatial-temporal communication between intracellular signaling pathways. Herein, we provide a contemporary overview of the significant roles that redox switches play in calcium signaling for orchestrated endothelial, smooth muscle, and red blood cell control of arterial vascular tone. Three interrelated themes are the focus: (a) smooth muscle to endothelial communication for vasoconstriction, (b) endothelial to smooth muscle cell cross talk for vasodilation, and (c) oxygen and red blood cell interregulation of vascular tone and blood flow. We intend for this thematic framework to highlight gaps in our current knowledge and potentially spark interest for cross-disciplinary studies moving forward. [ABSTRACT FROM AUTHOR]

In resistance arteries, endothelial cells (EC) make contact with smooth muscle cells (SMC), forming myoendothelial junctions (MEJ). Endothelial nitric oxide synthase (eNOS) is present in the luminal side of the EC (apical EC) and the basal side of the EC (MEJ). To test if these eNOS pools acted in sync or separately, we co-cultured ECs and SMCs, then stimulated SMCs with phenylephrine (PE). Adrenergic activation causes inositol [1,4,5] triphosphate (IP 3 ) to move from SMC to EC through gap junctions at the MEJ. PE increases MEJ eNOS phosphorylation (eNOS-P) at S1177, but not in EC. Conversely, we used bradykinin (BK) to increase EC calcium; this increased EC eNOS-P but did not affect MEJ eNOS-P. Inhibiting gap junctions abrogated the MEJ eNOS-P after PE, but had no effect on BK eNOS-P. Differential lipid composition between apical EC and MEJ may account for the compartmentalized eNOS-P response. Indeed, DAG and phosphatidylserine are both enriched in MEJ. These lipids are cofactors for PKC activity, which was significantly increased at the MEJ after PE. Because PKC activity also relies on endoplasmic reticulum (ER) calcium release, we used thapsigargin and xestospongin C, BAPTA, and PKC inhibitors, which caused significant decreases in MEJ eNOS-P after PE. Functionally, BK inhibited leukocyte adhesion and PE caused an increase in SMC cGMP. We hypothesize that local lipid composition of the MEJ primes PKC and eNOS-P for stimulation by PE, allowing for compartmentalized function of eNOS in the blood vessel wall. [ABSTRACT FROM AUTHOR]