Arachidonic Acid Evokes an Increase in Intracellular Ca<sup>2+</sup> Concentration and Nitric Oxide Production in Endothelial Cells from Human Brain Microcirculation
2019
Roberto Berra-Romani | Pawan Faris | Sharon Negri | Laura Botta | Tullio Genova | Francesco Moccia
It has long been known that the conditionally essential polyunsaturated arachidonic acid (AA) regulates cerebral blood flow (CBF) through its metabolites prostaglandin E2 and epoxyeicosatrienoic acid, which act on vascular smooth muscle cells and pericytes to vasorelax cerebral microvessels. However, AA may also elicit endothelial nitric oxide (NO) release through an increase in intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>). Herein, we adopted Ca<sup>2+</sup> and NO imaging, combined with immunoblotting, to assess whether AA induces intracellular Ca<sup>2+</sup> signals and NO release in the human brain microvascular endothelial cell line hCMEC/D3. AA caused a dose-dependent increase in [Ca<sup>2+</sup>]<sub>i</sub> that was mimicked by the not-metabolizable analogue, eicosatetraynoic acid. The Ca<sup>2+</sup> response to AA was patterned by endoplasmic reticulum Ca<sup>2+</sup> release through type 3 inositol-1,4,5-trisphosphate receptors, lysosomal Ca<sup>2+</sup> mobilization through two-pore channels 1 and 2 (TPC1-2), and extracellular Ca<sup>2+</sup> influx through transient receptor potential vanilloid 4 (TRPV4). In addition, AA-evoked Ca<sup>2+</sup> signals resulted in robust NO release, but this signal was considerably delayed as compared to the accompanying Ca<sup>2+</sup> wave and was essentially mediated by TPC1-2 and TRPV4. Overall, these data provide the first evidence that AA elicits Ca<sup>2+</sup>-dependent NO release from a human cerebrovascular endothelial cell line, but they seemingly rule out the possibility that this NO signal could acutely modulate neurovascular coupling.
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