G protein-coupled estrogen receptor agonist improves cerebral microvascular function after hypoxia/reoxygenation injury in male and female rats.
OBJECTIVE
Reduced risk and severity of stroke in adult females are thought to depend on normal levels of endogenous estrogen, which is a known neuro- and vasoprotective agent in experimental cerebral ischemia. Recently, a novel G protein-coupled estrogen receptor (GPER, formerly GPR30) has been identified and may mediate the vasomotor and -protective effects of estrogen. However, the signaling mechanisms associated with GPER in the cerebral microcirculation remain unclear. We investigated the mechanism of GPER-mediated vasoreactivity and also its vasoprotective effect after hypoxia/reoxygenation (H/RO) injury.


METHODS
Rat cerebral penetrating arterioles from both sexes were isolated, cannulated, and pressurized. Vessel diameters were recorded by computer-aided videomicroscopy. To investigate vasomotor mechanism of the GPER agonist (G-1), several inhibitors with or without endothelial impairment were tested. Ischemia/reperfusion injury was simulated using H/RO. Vasomotor responses to adenosine triphophate after H/RO were measured with or without G-1 and compared with controls.


RESULTS
G-1 produced a vasodilatory response, which was partially dependent on endothelium-derived nitric oxide (NO) but not arachidonic acid cascades and endothelial hyperpolarization factor. Attenuation of G-1-vasodilation by the NO synthase inhibitor and endothelium-impairment were greater in vessels from female than male animals. G-1 treatment after H/RO injury fully restored arteriolar dilation to adenosine triphophate compared with controls.


CONCLUSIONS
GPER agonist elicited dilation, which was partially caused by endothelial NO pathway and induced by direct relaxation of smooth muscle cells. Further, GPER agonist restored vessel function of arterioles after H/RO injury and may play an important role in the ability of estrogen to protect the cerebrovasculature against ischemia/reperfusion injury.
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Takahiro
T
Murata
Hans H
HH
Dietrich
Chuanxi
C
Xiang
Ralph G
RG
Dacey
D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology; D001921:Brain / Q000098:blood supply* / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D003517:Cyclopentanes / Q000494:pharmacology*; D004967:Estrogens / Q000502:physiology; D005260:Female; D008297:Male; D055806:Microvessels / Q000187:drug effects* / Q000503:physiopathology; D023421:Models, Animal; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors; D015427:Reperfusion Injury / Q000503:physiopathology*; D012737:Sex Factors; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; C568862:4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline; D052117:Benzodioxoles; D003517:Cyclopentanes; D004967:Estrogens; C520305:Gper1 protein, rat; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled