The incidence of fetal alcohol spectrum disorders (FASD) ranges from 20 to 50 per 1,000 live births in a worldwide studies of school-age children and is estimated to affect at least 1% of all births in the US (www.cdc.gov). The etiology of FASD is poorly understood, and is usually considered to have neuronal origin. Indeed, maternal alcohol consumption results in diminished neuronal migration, oligodenrocytes and microglial development. However, little attention is given to fetal cerebral circulation as a target of maternal drinking. Fetal cerebral blood flow is critical for oxygen and nutrient delivery to developing brain and vascular responses of cerebral arteries are fundamental in the fetal adaptation to the adverse intrauterine conditions. The experimental work in animal models showed vasodilating effect of maternal alcohol consumption in fetal cerebral arteries. The mechanism(s) of this effect remains unknown. Endocannabinoids (eCBs: anandamide, 2-arachydonoylglycerol) are powerful vasodilators in adult circulation, and our preliminary data show expression of eCB receptor CB1 in fetal blood vessels. Therefore, we hypothesize that maternal alcohol consumption during second half of gestation alters fetal cerebral artery contractility via eCB dependent mechanism(s). Using a primate model (baboon, Papio spp.) of pregnancy and combining Doppler examination of fetal cerebral blood flow, stable isotope dilution gas chromatography/mass spectrometry, immunohistochemistry, RT-PCR, pressurized cerebral artery diameter measurements and selective pharmacology, we will: 1) Establish whether maternal binge drinking during the second half of gestation alters key elements of the endocannabinoid system in fetal cerebral arteries: circulating level of anandamide and 2- arachydonoylglycerol, tissue expression of their metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively, and tissue expression of CB1 receptor for eCBs;2) Determine whether maternal binge drinking alters eCB-mediated control of vascular contractility and unveil underlying subcellular mechanism(s) by testing eCB-induced pressurized fetal cerebral artery diameter change in the presence of CB1 receptor antagonist, calcium/voltage-gated potassium (BK) and voltage-gated Ca2+ channel blockers. Our study will establish for the first time role of fetal cerebral artery eCB system in the respons of fetal circulation to maternal alcohol consumption. Successful completion of the proposed studies will open conceptually new venue for the prevention and treatment of FASD. Current work will be also highly relevant in the lieu of rapidly growing area of eCB manipulation for treatment of obesity, cardiovascular and neurological disorders, as pharmaceutical alteration of vascular eCB system may cause adverse effects on fetal brain development.
Current proposal for the first time identifies fetal cerebral artery endocannabinoid (eCB) system as a target for maternal alcohol consumption and putative cause for fetal alcohol spectrum disorders (FASD). Our study will open a conceptually new venue for prevention and treatment of FASD. Current work will be also highly relevant in the lieu of rapidly growing area of eCB manipulation for treatment of obesity, cardiovascular and neurological disorders, as pharmaceutical alteration of eCB system may cause adverse effects on fetal brain development.