Prostaglandin E2 at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles: implications for neurovascular coupling responses

Abstract

There is considerable controversy regarding the vasoactive action of prostaglandin E2 (PGE2). On the one hand, indirect evidence implicates that astrocytic release of PGE2 contributes to neurovascular coupling responses mediating functional hyperemia in the brain. On the other hand, overproduction of PGE2 was also reported to contribute to cerebral vasospasm associated with subarachnoid hemorrhage. The present study was conducted to resolve this controversy by determining the direct vasoactive effects of PGE2 in resistance‐sized human cerebral parenchymal arterioles.To achieve this goal PGE2‐induced isotonic responses were assessed in parenchymal arterioles isolated from fronto‐temporo‐parietal cortical tissues surgically removed from patients and expression of PGE2 receptors were examined.In functionally intact parenchymal arterioles lower concentrations of PGE2 (from 10−8 to 10−6 mol/l) caused significant, endothelium‐independent vasorelaxation, which was inhibited by the EP4 receptor blocker BGC201531. In contrast, higher concentrations of PGE2 evoked significant EP1‐dependent vasoconstriction, which could not be reversed by the EP4 receptor agonist CAY10598. We also confirmed previous observations that PGE2 primarily evokes constriction in intracerebral arterioles isolated from R. norvegicus. Importantly, vascular mRNA expression of vasodilator EP4 receptors was significantly higher than that of vasoconstrictor EP1 receptors in human cerebral arterioles. In contrast, rat vessels expressed predominantly EP1 receptors.PGE2 at low concentrations dilates whereas at higher concentrations constricts human cerebral parenchymal arterioles. This bimodal vasomotor response is consistent with both the proposed vasodilator role of PGE2 during functional hyperemia and its putative role in cerebral vasospasm associated with subarachnoid hemorrhage in human subjects.Support or Funding InformationThis work was supported by grants from the National Research, Development and Innovation Office to PT (NKFI‐FK123798) and AK (K108444), the Hungarian Academy of Sciences Bolyai Research Scholarship BO/00634/15 to PT, the PTE AOK‐KA 3/2016 04.01/F to PT, the ÚNKP‐18‐4‐PTE‐6 New National Excellence Program of the Ministry of Human Capacities, Higher Education Institutional Excellence Programme – Grant No. 20765‐3/2018/FEKUTSTRAT, EFOP‐3.6.2.‐16‐2017‐00008, GINOP‐2.3.2‐15‐2016‐00048 and GINOP‐2.3.3‐15‐2016‐00032 to PT and AB, the Hungarian National Brain Research Program Grant No. 2017‐1.2.1‐NKP‐2017‐00002 to AB; the Marie Curie Actions SMARTER 7th Framework Program of the European Union 606998 to NSz and AK, National Institute of Health R01‐AG055395, R01‐NS100782, R01‐AT006526 to ZU.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.