Nitrative stress is an important regulator of vascular tone. We have recently described that
trans-arachidonic acids (
TAA) are major products of NO
2·–mediated isomerization of arachidonic acid in cell membranes and that nitrative stress increases
TAA levels leading to neural microvascular degeneration. In the present study, we explored whether
TAA exert acute effects on neuromicrovascular tone and investigated potential mechanisms thereof.
TAA induced an endothelium-dependent vasorelaxation of rat brain pial microvasculature. This vasorelaxation was independent of nitric oxide, prostanoids, lipoxygenase products, and CYP
450 metabolite
trans-hydroxyeicosatetraenoic acids. However, inhibition of heme oxygenase (using zinc protoporphyrin IX) and of dependent soluble guanylate cyclase (sGC; using ODQ) significantly diminished (by
70 % ) the
TAA-induced vasorelaxation. Consistent with these findings,
TAA stimulated heme oxygenase (HO)-2-dependent bilirubin (using siRNA HO-2) and cGMP formation, and the HO product carbon monoxide (using CO-releasing CORM-2) reproduced the sGC-dependent cGMP formation and vasorelaxation. Further exploration revealed that
TAA-induced vasorelaxation and bilirubin formation (HO activation) were nearly abrogated by large-conductance calcium-dependent potassium channels (BK
Ca) (using TEA and iberiotoxin). Opening of BK
Ca with the selective activator NS1619 induced a concentration-dependent vasorelaxation, which was inhibited by HO and sGC inhibitors. Coimmunoprecipitation suggested a molecular complex interaction between BK
Ca and HO-2 (but not HO-1). Collectively, these findings identify new properties of
TAA, specifically cerebral vasorelaxation through interactive activation of BK
Ca with HO-2 and, in turn, sGC. Our findings provide new insights into the characterization of nitrative stress-derived
TAA products, by showing they can act as acute mediators of nitrative stress on neurovascular tone.