title: Maternal alcohol consumption in pregnancy enhances arterial stiffness and alters vasodilator function that varies between vascular beds in fetal sheep.
abstract: While the impact of alcohol consumption by pregnant women on fetal neurodevelopment has received much attention, the effects on the cardiovascular system are not well understood. We hypothesised that repeated exposure to alcohol (ethanol) in utero would alter fetal arterial reactivity and wall stiffness, key mechanisms leading to cardiovascular disease in adulthood. Ethanol (0.75 g (kg body weight)(-1)) was infused intravenously into ewes over 1 h daily for 39 days in late pregnancy (days 95-133 of pregnancy, term ∼147 days). Maternal and fetal plasma ethanol concentrations at the end of the hour were ∼115 mg dl(-1), and then declined to apparent zero over 8 h. At necropsy (day 134), fetal body weight and fetal brain-body weight ratio were not affected by alcohol infusion. Small arteries (250-300 μm outside diameter) from coronary, renal, mesenteric, femoral (psoas) and cerebral beds were isolated. Endothelium-dependent vasodilatation sensitivity was reduced 10-fold in coronary resistance arteries, associated with a reduction in endothelial nitric oxide synthase mRNA (P = 0.008). Conversely, vasodilatation sensitivity was enhanced 10-fold in mesenteric and renal resistance arteries. Arterial stiffness was markedly increased (P = 0.0001) in all five vascular beds associated with an increase in elastic modulus and, in cerebral vessels, with an increase in collagen Iα mRNA. Thus, we show for the first time that fetal arteries undergo marked and regionally variable adaptations as a consequence of repeated alcohol exposure. These alcohol-induced vascular effects occurred in the apparent absence of fetal physical abnormalities or fetal growth restriction.
authors.affiliation: Departments of Physiology, Monash University, Clayton, Victoria, 3800, Australia helena.parkington@monash.edu.
authors.forename: Helena C
authors.initials: HC
authors.lastname: Parkington
authors.affiliation: Departments of Physiology, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Kenna
authors.affiliation: Anatomy and Developmental Biology, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Foula
authors.initials: F
authors.lastname: Sozo
authors.affiliation: Departments of Physiology, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Harold A
authors.initials: HA
authors.lastname: Coleman
authors.affiliation: Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: Bocking
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Canada.
authors.forename: James F
authors.initials: JF
authors.lastname: Brien
authors.affiliation: Anatomy and Developmental Biology, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Harding
authors.affiliation: Ritchie Centre, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
authors.affiliation: Royal Children's Hospital, Flemington Road, Melbourne, Victoria, 3052, Australia.
authors.forename: Ruth
authors.initials: R
authors.lastname: Morley
authors.affiliation: Departments of Physiology, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Marianne
authors.initials: M
authors.lastname: Tare
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000098:blood supply / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000502:physiology; D041981:Gastrointestinal Tract / Q000098:blood supply / Q000502:physiology; D007668:Kidney / Q000098:blood supply / Q000502:physiology; D008431:Maternal-Fetal Exchange; D018482:Muscle, Skeletal / Q000098:blood supply / Q000502:physiology; D011247:Pregnancy; D012756:Sheep; D059289:Vascular Stiffness / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
references.citation: J Physiol. 2010 Jun 1;588(Pt 11):1997-2010
references.pmid: 20403978
references.citation: Obstet Gynecol. 2008 Aug;112(2 Pt 1):277-83
references.pmid: 18669723
references.citation: Diabetologia. 2004 Jun;47(6):1038-46
references.pmid: 15184978
references.citation: Teratology. 1991 Jun;43(6):591-600
references.pmid: 1882350
references.citation: Expert Rev Cardiovasc Ther. 2009 May;7(5):499-506
references.pmid: 19419257
references.citation: Alcohol. 2002 Feb;26(2):75-81
references.pmid: 12007582
references.citation: Stroke. 2001 Jan;32(1):249-57
references.pmid: 11136944
references.citation: J Physiol. 2007 Feb 1;578(Pt 3):871-81
references.pmid: 17124269
references.citation: J Am Soc Nephrol. 2010 Nov;21(11):1891-902
references.pmid: 20829403
references.citation: Am J Physiol Heart Circ Physiol. 2012 Aug 15;303(4):H414-21
references.pmid: 22730388
references.citation: Am J Hypertens. 2005 Jun;18(6):792-6
references.pmid: 15925738
references.citation: Arterioscler Thromb Vasc Biol. 2005 May;25(5):932-43
references.pmid: 15731494
references.citation: Pediatr Nephrol. 1990 Jan;4(1):48-51
references.pmid: 2206881
references.citation: Hypertens Res. 2004 Sep;27(9):669-73
references.pmid: 15750261
references.citation: Am J Obstet Gynecol. 1985 Jul 1;152(5):583-90
references.pmid: 4014353
references.citation: J Immunol. 2009 Oct 15;183(8):5232-43
references.pmid: 19783678
references.citation: Pediatr Res. 2007 Apr;61(4):456-61
references.pmid: 17515871
references.citation: Clin J Am Soc Nephrol. 2008 Jan;3(1):184-92
references.pmid: 18178784
references.citation: PLoS One. 2010 Feb 17;5(2):e9250
references.pmid: 20174656
references.citation: Lancet. 1997 Sep 27;350(9082):953-5
references.pmid: 9314885
references.citation: Curr Drug Targets. 2007 Aug;8(8):914-22
references.pmid: 17691928
references.citation: Neonatology. 2010;97(3):204-11
references.pmid: 19864927
references.citation: QJM. 2008 Nov;101(11):881-7
references.pmid: 18790817
references.citation: Alcohol Clin Exp Res. 2007 Sep;31(9):1574-80
references.pmid: 17624995
references.citation: J Hypertens. 2006 May;24(5):875-80
references.pmid: 16612249
references.citation: Clin Exp Pharmacol Physiol. 2001 Nov;28(11):948-51
references.pmid: 11703403
references.citation: Antioxid Redox Signal. 2011 May 1;14(9):1675-86
references.pmid: 20673125
references.citation: Am J Physiol Regul Integr Comp Physiol. 2008 Aug;295(2):R568-74
references.pmid: 18565833
references.citation: Cardiovasc Toxicol. 2007;7(4):247-54
references.pmid: 17990129
references.citation: Acta Physiol (Oxf). 2009 Jun;196(2):193-222
references.pmid: 19220204
references.citation: J Pharmacol Exp Ther. 2006 Aug;318(2):819-27
references.pmid: 16651399
references.citation: Stroke. 2002 Dec;33(12):2992-8
references.pmid: 12468802
references.citation: Exp Physiol. 2007 Sep;92(5):933-43
references.pmid: 17526556
references.citation: Alcohol Clin Exp Res. 2001 Feb;25(2):269-76
references.pmid: 11236842
references.citation: Alcohol Clin Exp Res. 2007 Jul;31(7):1099-105
references.pmid: 17488323
references.citation: Circulation. 2009 Jul 21;120(3):237-44
references.pmid: 19597054
references.citation: Curr Drug Abuse Rev. 2008 Jan;1(1):47-55
references.pmid: 19630705
references.citation: J Pediatr. 2004 Nov;145(5):635-40
references.pmid: 15520764
references.citation: Br J Pharmacol. 2009 Jun;157(4):540-50
references.pmid: 19338582
references.citation: Alcohol Alcohol. 2007 Nov-Dec;42(6):629-34
references.pmid: 17660522
references.citation: Circ Res. 2008 Apr 25;102(8):933-41
references.pmid: 18309099
references.citation: Pediatrics. 1994 Aug;94(2 Pt 1):209-12
references.pmid: 8036075
references.citation: Pediatr Res. 1997 Jul;42(1):39-45
references.pmid: 9212035
references.citation: Obstet Gynecol Surv. 2013 Jan;68(1):62-9
references.pmid: 23322082
references.citation: Arch Intern Med. 2006 Dec 11-25;166(22):2437-45
references.pmid: 17159008
references.citation: Hypertension. 2001 May;37(5):1236-41
references.pmid: 11358934
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 Oct;301(4):R926-36
references.pmid: 21715699
references.citation: Hypertension. 2003 Oct;42(4):768-74
references.pmid: 12874089
references.citation: Neurosci Lett. 2002 Dec 6;334(1):21-4
references.pmid: 12431766
references.citation: Alcohol Clin Exp Res. 2007 Feb;31(2):276-84
references.pmid: 17250620