Inositol trisphosphate dynamics underlie physiological calcium signals within the coronary artery endothelium

The arterial endothelium modulates smooth muscle tone in response to its local hemodynamic environment. This process is critical to normal vascular function, and is impaired by endothelial cell injury in coronary artery disease. Last year, we discovered a unique mode of calcium signaling of the porcine coronary artery endothelium, characterized by a pattern of continuous, cell‐wide calcium waves in the absence of agonist stimulation. Stimulation with substance P (10 −13 to 10 −6 ml/L) amplified this pattern to match dose‐dependent vessel relaxation responses. Here, we investigated the mechanism underlying the formation of this characteristic pattern of endothelial calcium waves with confocal microscopy, utilizing both pharmacological and computational approaches. We found that coronary endothelial cell calcium waves were mediated by inositol trisphosphate receptors (IP3R), which exhibited distinct intracellular isoform distributions. The distribution of the type 1 IP3R isoform corresponded to the area (33.9 ± 2.6 μm 2 ) of propagating calcium waves, including perinuclear IP3R clustering at subcellular sites of constitutively elevated calcium. We utilized a computational model of calcium signaling that included this distinct IP3R distribution, and discovered that cell‐wide waves formed only if intracellular concentration gradients of inositol trisphosphate (IP3) were present along the longitudinal cell axis. Importantly, we found that production and diffusion of IP3 from a focal intracellular source was sufficient to initiate a calcium wave event with the same propagation velocity curve (mean: 6.08 ± 0.61 μm/s) of the experimentally‐observed wave. Furthermore, amplification of IP3 production in our model resulted in an increase of the frequency of elementary wave events which reflected the dose‐dependent expansion of calcium activity induced by substance P. These results indicate a fundamental role for IP3 dynamics as a physiological mediator of vascular responses, underlying both the initiation and expansion of unique endothelial calcium signal modalities. Support or Funding Information This work was supported by NIH grants: HL136869, HL085887, and S10RR027535. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .