Accumulating evidence supports a role for microvascular dysfunction in the development of delayed cerebral ischemia following subarachnoid hemorrhage (SAH). The mechanism underlying delayed microvascular vasospasm (dMVS) is unknown. Using 3-dimensional, quantitative optical microangiography (OMAG), we assessed early and delayed changes in perfusion and dimensions of cerebrocortical microvessels in a mouse model of SAH. We tested the hypothesis that the development of dMVS after SAH is linked to changes in expression of soluble epoxide hydrolase (sEH), a key enzyme in the metabolism of a group of vasodilator eicosanoids called epoxyeicosatrienoic acids (EETs). Wild-type (WT, n=6) mice and mice lacking the sEH gene (sEHKO, n=4) were subjected to endovascular perforation to induce SAH, and followed for 72 hours to assess dMVS using OMAG. At 24 hours after SAH, no apparent change in cortical perfusion was observed in either WT or sEHKO mice compared to baseline (p>0.05), although both strains experienced constriction of individual cortical microvessels (-7.4 +/- 1.1% and -6.2 +/- 1.2% change from baseline (p<0.05) in WT and sEHKO mice respectively). At 72 hours after SAH, WT mice developed further microvascular vasoconstriction (-9.6 +/- 1% change from baseline (p<0.05 compared to baseline and 24h) ) and sustained a significant decrease (14.5 +/- 4.5% ) in cortical perfusion compared to baseline perfusion (p<0.05), whereas sEHKO mice did not show further changes in microvascular diameters, and were protected from the delayed drop in cortical perfusion. We conclude that genetic deletion of sEH can protect against dMVS in a mouse model of SAH. Our results suggest that EETs pathway may be involved in the pathogenesis of dMVS following SAH.
Testing Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage: Rare Diseases, Orphan Drugs, the Conundrum
