In the vascular wall coupling between endothelial (EC) and smooth muscle (SMC) cells generates complex feedback control loops that regulate arteriolar diameter and blood flow. Ample experimental studies investigate signaling pathways involved in the regulation of vascular tone, but there are far less theoretical studies to assist in the analysis of experimental data. We developed biophysical models of Ca2+ dynamics in EC and SMC of the rat mesenteric microcirculation that incorporate NO dependent signaling. Isolated single cell models were validated against experimental data and then integrated through myoendothelial gap junctions and NO diffusion. Stimulation of SMC with extracellular K+ or norepinephrine (NE) evokes Ca2+ oscillations if the resulting increase in intracellular concentration ([Ca2+]i) falls within the 200–300nM range. EC stimulation in NE-preconstricted vessels repolarizes SMC and reduces [Ca2+]i by 1) transmitting a hyperpolarizing current through the gap junctions and/or 2) by NO-induced activation of SM KCa channels. IP3 coupling was necessary for transmitting information from SM to EC and generates negative feedback loops capable of reducing NE-induced SM [Ca2+]i transients. Partial Na+−K+ pump inhibition, simulating effect of ouabain in salt sensitive hypertension, caused Na+ accumulation, Na+−Ca2+ exchanger reversal, hyperreactivity to NE and SM desensitization to NO. The model reproduces a variety of experimental findings and proposes testable hypothesis for optimal NO delivery strategies. Supported by AHA grant NSDG043506N.