Prostaglandin E2, a postulated astrocyte-derived neurovascular coupling agent, constricts rather than dilates parenchymal arterioles

Abstract

It has been proposed that prostaglandin E(2) (PGE(2)) is released from astrocytic endfeet to dilate parenchymal arterioles through activation of prostanoid (EP(4)) receptors during neurovascular coupling. However, the direct effects of PGE(2) on isolated parenchymal arterioles have not been tested. Here, we examined the effects of PGE(2) on the diameter of isolated pressurized parenchymal arterioles from rat and mouse brain. Contrary to the prevailing assumption, we found that PGE(2) (0.1, 1, and 5 μmol/L) constricted rather than dilated parenchymal arterioles. Vasoconstriction to PGE(2) was prevented by inhibitors of EP(1) receptors. These results strongly argue against a direct role of PGE(2) on arterioles during neurovascular coupling.

Figure 1

(A–D) Rat and mouse parenchymal arterioles (PA) constrict in response to prostaglandin E₂ (PGE₂). (A) Recording of the internal diameter of a pressurized (40 mm Hg) rat parenchymal arteriole during the perfusion of PGE₂ (0.1, 1, and 5 μmol/L), added noncumulatively. (B) Summary data (means±SEMs) showing changes in luminal diameter expressed as percentages relative to baseline diameter; the number of experiments is indicated in parentheses (**P<0.01, NS indicates nonsignificant). (C) Recordings of the internal diameter of pressurized (40 mm Hg) mouse parenchymal arterioles during the perfusion of PGE₂ (1 μmol/L) with and without EP receptor inhibitors. Upper trace: nonselective EP₁, EP₂, and EP₃ receptor antagonist AH6809 (10 μmol/L). Bottom trace: selective EP₁ antagonist SC51322 (1 μmol/L). Both nonselective inhibition of EP_1–3 receptors and specific inhibition of EP₁ completely prevented PGE₂-induced vasoconstriction in mouse parenchymal arterioles. Adenosine (10 μmol/L; top trace) and NS309 (1 μmol/L; bottom trace) were included as positive controls. (D) Summary data (means±SEMs) showing change in luminal diameter; the number of experiment is indicated in parentheses (**P<0.01, ***P<0.001). (E, F) Prostacyclin (PGI₂) dilates mouse parenchymal arterioles. (E) Typical recordings of the internal diameter of pressurized (40 mm Hg) parenchymal arterioles during the perfusion of PGI₂ (1, 3, and 10 μmol/L), added noncumulatively. (F) Summary data (means±SEMs) showing change in luminal diameter induced by adenosine with and without A_2A receptor antagonist ZM241385 and PGI₂; the number of experiments is indicated in parentheses (*P<0.05, **P<0.01, NS indicates nonsignificant).