title: Increased angiotensin II contraction of the uterine artery at early gestation in a transgenic model of hypertensive pregnancy is reduced by inhibition of endocannabinoid hydrolysis.
abstract: Increased vascular sensitivity to angiotensin II (Ang II) is a marker of a hypertensive human pregnancy. Recent evidence of interactions between the renin-angiotensin system and the endocannabinoid system suggests that anandamide and 2-arachidonoylglycerol may modulate Ang II contraction. We hypothesized that these interactions may contribute to the enhanced vascular responses in hypertensive pregnancy. We studied Ang II contraction in isolated uterine artery (UA) at early gestation in a rat model that mimics many features of preeclampsia, the transgenic human angiotensinogen×human renin (TgA), and control Sprague-Dawley rats. We determined the role of the cannabinoid receptor 1 by blockade with SR171416A, and the contribution of anandamide and 2-arachidonoylglycerol degradation to Ang II contraction by inhibiting their hydrolyzing enzyme fatty acid amide hydrolase (with URB597) or monoacylglycerol lipase (with JZL184), respectively. TgA UA showed increased maximal contraction and sensitivity to Ang II that was inhibited by indomethacin. Fatty acid amide hydrolase blockade decreased Ang IIMAX in Sprague-Dawley UA, and decreased both Ang IIMAX and sensitivity in TgA UA. Monoacylglycerol lipase blockade had no effect on Sprague-Dawley UA and decreased Ang IIMAX and sensitivity in TgA UA. Blockade of the cannabinoid receptor 1 in TgA UA had no effect. Immunolocalization of fatty acid amide hydrolase and monoacylglycerol lipase showed a similar pattern between groups; fatty acid amide hydrolase predominantly localized in endothelium and monoacylglycerol lipase in smooth muscle cells. We demonstrated an increased Ang II contraction in TgA UA before initiation of the hypertensive phenotype. Anandamide and 2-arachidonoylglycerol reduced Ang II contraction in a cannabinoid receptor 1-independent manner. These renin-angiotensin system-endocannabinoid system interactions may contribute to the enhanced vascular reactivity in early stages of hypertensive pregnancy.
authors.affiliation: From Departments of Obstetrics and Gynecology (V.M.P.), Surgical Sciences (L.M.Y., J.V., C.M.M., K.B.B.), and Physiology and Pharmacology (K.B.B.), Hypertension and Vascular Research Center, and Departments of Obstetrics and Gynecology (V.M.P.) and Physiology and Pharmacology (A.C.H.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Life Sciences, Biomedical Research Infrastructure Center, Winston-Salem State University, NC (V.M.P.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B.); and Charité University Hospital Berlin, Berlin, Germany (M.B., R.D.). vpulgar@wakehealth.edu.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Pulgar
authors.affiliation: From Departments of Obstetrics and Gynecology (V.M.P.), Surgical Sciences (L.M.Y., J.V., C.M.M., K.B.B.), and Physiology and Pharmacology (K.B.B.), Hypertension and Vascular Research Center, and Departments of Obstetrics and Gynecology (V.M.P.) and Physiology and Pharmacology (A.C.H.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Life Sciences, Biomedical Research Infrastructure Center, Winston-Salem State University, NC (V.M.P.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B.); and Charité University Hospital Berlin, Berlin, Germany (M.B., R.D.).
authors.forename: Liliya M
authors.initials: LM
authors.lastname: Yamaleyeva
authors.affiliation: From Departments of Obstetrics and Gynecology (V.M.P.), Surgical Sciences (L.M.Y., J.V., C.M.M., K.B.B.), and Physiology and Pharmacology (K.B.B.), Hypertension and Vascular Research Center, and Departments of Obstetrics and Gynecology (V.M.P.) and Physiology and Pharmacology (A.C.H.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Life Sciences, Biomedical Research Infrastructure Center, Winston-Salem State University, NC (V.M.P.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B.); and Charité University Hospital Berlin, Berlin, Germany (M.B., R.D.).
authors.forename: Jasmina
authors.initials: J
authors.lastname: Varagic
authors.affiliation: From Departments of Obstetrics and Gynecology (V.M.P.), Surgical Sciences (L.M.Y., J.V., C.M.M., K.B.B.), and Physiology and Pharmacology (K.B.B.), Hypertension and Vascular Research Center, and Departments of Obstetrics and Gynecology (V.M.P.) and Physiology and Pharmacology (A.C.H.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Life Sciences, Biomedical Research Infrastructure Center, Winston-Salem State University, NC (V.M.P.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B.); and Charité University Hospital Berlin, Berlin, Germany (M.B., R.D.).
authors.forename: Carolynne M
authors.initials: CM
authors.lastname: McGee
authors.affiliation: From Departments of Obstetrics and Gynecology (V.M.P.), Surgical Sciences (L.M.Y., J.V., C.M.M., K.B.B.), and Physiology and Pharmacology (K.B.B.), Hypertension and Vascular Research Center, and Departments of Obstetrics and Gynecology (V.M.P.) and Physiology and Pharmacology (A.C.H.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Life Sciences, Biomedical Research Infrastructure Center, Winston-Salem State University, NC (V.M.P.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B.); and Charité University Hospital Berlin, Berlin, Germany (M.B., R.D.).
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: From Departments of Obstetrics and Gynecology (V.M.P.), Surgical Sciences (L.M.Y., J.V., C.M.M., K.B.B.), and Physiology and Pharmacology (K.B.B.), Hypertension and Vascular Research Center, and Departments of Obstetrics and Gynecology (V.M.P.) and Physiology and Pharmacology (A.C.H.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Life Sciences, Biomedical Research Infrastructure Center, Winston-Salem State University, NC (V.M.P.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B.); and Charité University Hospital Berlin, Berlin, Germany (M.B., R.D.).
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.affiliation: From Departments of Obstetrics and Gynecology (V.M.P.), Surgical Sciences (L.M.Y., J.V., C.M.M., K.B.B.), and Physiology and Pharmacology (K.B.B.), Hypertension and Vascular Research Center, and Departments of Obstetrics and Gynecology (V.M.P.) and Physiology and Pharmacology (A.C.H.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Life Sciences, Biomedical Research Infrastructure Center, Winston-Salem State University, NC (V.M.P.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B.); and Charité University Hospital Berlin, Berlin, Germany (M.B., R.D.).
authors.forename: Allyn C
authors.initials: AC
authors.lastname: Howlett
authors.affiliation: From Departments of Obstetrics and Gynecology (V.M.P.), Surgical Sciences (L.M.Y., J.V., C.M.M., K.B.B.), and Physiology and Pharmacology (K.B.B.), Hypertension and Vascular Research Center, and Departments of Obstetrics and Gynecology (V.M.P.) and Physiology and Pharmacology (A.C.H.), Wake Forest School of Medicine, Winston-Salem, NC; Department of Life Sciences, Biomedical Research Infrastructure Center, Winston-Salem State University, NC (V.M.P.); Max Delbrück Center for Molecular Medicine, Berlin, Germany (M.B.); and Charité University Hospital Berlin, Berlin, Germany (M.B., R.D.).
authors.forename: K Bridget
authors.initials: KB
authors.lastname: Brosnihan
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D002219:Carbamates / Q000494:pharmacology; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005989:Glycerides / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D046110:Hypertension, Pregnancy-Induced / Q000503:physiopathology*; D008297:Male; D050178:Monoglycerides / Q000037:antagonists & inhibitors / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000037:antagonists & inhibitors / Q000378:metabolism; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D055988:Uterine Artery / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000804:Angiotensin II; D001095:Arachidonic Acids; D001549:Benzamides; D052117:Benzodioxoles; D002219:Carbamates; D063388:Endocannabinoids; D005989:Glycerides; D050178:Monoglycerides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C534333:JZL 184; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C094503:glyceryl 2-arachidonate; C078814:anandamide
keywords: endocannabinoids; fatty-acid amide hydrolase; high-risk pregnancy; monoacylglycerol lipases