TY - JOUR
T1 - Maternal alcohol exposure during mid-pregnancy dilates fetal cerebral arteries via endocannabinoid receptors
AU - Seleverstov, Olga
AU - Tobiasz, Ana
AU - Jackson, J. Scott
AU - Sullivan, Ryan
AU - Ma, Dejian
AU - Sullivan, J. Pierce
AU - Davison, Steven
AU - Akkhawattanangkul, Yada
AU - Tate, Danielle L.
AU - Costello, Terry
AU - Barnett, Stacey
AU - Li, Wei
AU - Mari, Giancarlo
AU - Dopico, Alex M.
AU - Bukiya, Anna N.
N1 - Funding Information:
The authors deeply thank Dr. Natalia Schlabritz-Lutsevich for her contribution to the conceptual design of the work and development of the binge alcohol infusion protocol in the baboon model of pregnancy at UT HSC. The authors also thank Shivantika Bisen and Jennifer Chang for their assistance in preparation of experimental saline solutions. This work was supported by NIH R21 AA022433 (ANB), and in part by the Office of the Director, National Institutes of Health, under Award Number P40OD010988. The LC-MS/MS instrument was acquired via shared instrumentation grant S10OD016226, Office of the Director, National Institutes of Health. The authors would like to dedicate the findings of this work to the memory of Terry Costello, who passed away unexpectedly during the revision of this manuscript.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/6
Y1 - 2017/6
N2 - Prenatal alcohol exposure often results in fetal alcohol syndrome and fetal alcohol spectrum disorders. Mechanisms of fetal brain damage by alcohol remain unclear. We used baboons (Papio spp.) to study alcohol-driven changes in the fetal cerebral artery endocannabinoid system. Pregnant baboons were subjected to binge alcohol exposure via gastric infusion three times during a period equivalent to the second trimester of human pregnancy. A control group was infused with orange-flavored drink that was isocaloric to the alcohol-containing solution. Cesarean sections were performed at a time equivalent to the end of the second trimester of human pregnancy. Fetal cerebral arteries were harvested and subjected to in vitro pressurization followed by pharmacological profiling. During each alcohol-infusion episode, maternal blood alcohol concentrations (BAC) reached 80 mg/dL, that is, equivalent to the BAC considered legal intoxication in humans. Circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) remained unchanged. Ultrasound studies on pregnant mothers revealed that fetal alcohol exposure decreased peak systolic blood velocity in middle cerebral arteries when compared to pre-alcohol levels. Moreover, ethanol-induced dilation was observed in fetal cerebral arteries pressurized in vitro. This dilation was abolished by the mixture of AM251 and AM630, which block cannabinoid receptors 1 and 2, respectively. In the presence of AM251, the cannabinoid receptor agonist AEA evoked a higher, concentration-dependent dilation of cerebral arteries from alcohol-exposed fetuses. The difference in AEA-induced cerebral artery dilation vanished in the presence of AM630. CB1 and CB2 receptor mRNA and protein levels were similar in cerebral arteries from alcohol-exposed and control-exposed fetuses. In summary, alcohol exposure dilates fetal cerebral arteries via endocannabinoid receptors and results in an increased function of CB2.
AB - Prenatal alcohol exposure often results in fetal alcohol syndrome and fetal alcohol spectrum disorders. Mechanisms of fetal brain damage by alcohol remain unclear. We used baboons (Papio spp.) to study alcohol-driven changes in the fetal cerebral artery endocannabinoid system. Pregnant baboons were subjected to binge alcohol exposure via gastric infusion three times during a period equivalent to the second trimester of human pregnancy. A control group was infused with orange-flavored drink that was isocaloric to the alcohol-containing solution. Cesarean sections were performed at a time equivalent to the end of the second trimester of human pregnancy. Fetal cerebral arteries were harvested and subjected to in vitro pressurization followed by pharmacological profiling. During each alcohol-infusion episode, maternal blood alcohol concentrations (BAC) reached 80 mg/dL, that is, equivalent to the BAC considered legal intoxication in humans. Circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) remained unchanged. Ultrasound studies on pregnant mothers revealed that fetal alcohol exposure decreased peak systolic blood velocity in middle cerebral arteries when compared to pre-alcohol levels. Moreover, ethanol-induced dilation was observed in fetal cerebral arteries pressurized in vitro. This dilation was abolished by the mixture of AM251 and AM630, which block cannabinoid receptors 1 and 2, respectively. In the presence of AM251, the cannabinoid receptor agonist AEA evoked a higher, concentration-dependent dilation of cerebral arteries from alcohol-exposed fetuses. The difference in AEA-induced cerebral artery dilation vanished in the presence of AM630. CB1 and CB2 receptor mRNA and protein levels were similar in cerebral arteries from alcohol-exposed and control-exposed fetuses. In summary, alcohol exposure dilates fetal cerebral arteries via endocannabinoid receptors and results in an increased function of CB2.
KW - Baboon pregnancy
KW - Binge drinking during pregnancy
KW - Fetal alcohol exposure
KW - Fetal cerebral artery
KW - Maternal alcohol consumption
UR - http://www.scopus.com/inward/record.url?scp=85019945204&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019945204&partnerID=8YFLogxK
U2 - 10.1016/j.alcohol.2017.01.014
DO - 10.1016/j.alcohol.2017.01.014
M3 - Article
C2 - 28554529
AN - SCOPUS:85019945204
SN - 0741-8329
VL - 61
SP - 51
EP - 61
JO - Alcohol
JF - Alcohol
ER -