Activation of angiotensin type 2 receptor attenuates testosterone-induced hypertension and uterine vascular resistance in pregnant rats†.
AT2 receptors
angiotensin
blood flow
endothelium
fetus
preeclampsia
pregnancy
testosterone
vascular function
Journal
Biology of reproduction
ISSN: 1529-7268
Titre abrégé: Biol Reprod
Pays: United States
ID NLM: 0207224
Informations de publication
Date de publication:
02 07 2021
02 07 2021
Historique:
received:
23
12
2020
revised:
23
02
2021
accepted:
16
03
2021
pubmed:
20
3
2021
medline:
24
12
2021
entrez:
19
3
2021
Statut:
ppublish
Résumé
Preeclampsia is a pregnancy-related hypertensive disorder with unclear mechanisms. While hypersensitivity to angiotensin II via vasoconstrictive angiotensin type-1 receptor (AT1R) is observed in preeclampsia, the importance of vasodilatory angiotensin type-2 receptor (AT2R) in the control of vascular dysfunction is less clear. We assessed whether AT1R, AT2R, and endothelial nitric oxide synthase (eNOS) expression are altered in placental vessels of preeclamptic women and tested if ex vivo incubation with AT2R agonist Compound 21 (C21; 1 μM) could restore AT1R, AT2R, and eNOS balance. Further, using a rat model of gestational hypertension induced by elevated testosterone, we examined whether C21 (1 μg/kg/day, oral) could preserve AT1R and AT2R balance and improve blood pressure, uterine artery blood flow, and vascular function. Western blots revealed that AT1R protein level was higher while AT2R and eNOS protein were reduced in preeclamptic placental vessels, and AT2R agonist C21 decreased AT1R and increased AT2R and eNOS protein levels in preeclamptic vessels. In testosterone dams, blood pressure was higher, and uterine artery blood flow was reduced, and C21 treatment reversed these levels similar to those in controls dams. C21 attenuated the exaggerated Ang II contraction and improved endothelium-dependent vasorelaxation in uterine arteries of testosterone dams. These C21-mediated vascular effects were associated with decreased AT1R and increased AT2R and eNOS protein levels. C21 also increased serum nitrate/nitrite and bradykinin production in testosterone dams and attenuated the fetoplacental growth restriction. Thus, AT1R upregulation and AT2R downregulation are observed in preeclampsia and testosterone model, and increasing AT2R activity could help restore AT1R and AT2R balance and improve gestational vascular function.
Identifiants
pubmed: 33739377
pii: 6178705
doi: 10.1093/biolre/ioab051
pmc: PMC8660162
doi:
Substances chimiques
Agtr1a protein, rat
0
Agtr2 protein, rat
0
Receptor, Angiotensin, Type 1
0
Receptor, Angiotensin, Type 2
0
Testosterone
3XMK78S47O
Nitric Oxide Synthase Type III
EC 1.14.13.39
Nos3 protein, rat
EC 1.14.13.39
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
192-203Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL119869
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL134779
Pays : United States
Organisme : National Institute of Health
ID : HL134779
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Références
Hypertension. 2013 Mar;61(3):647-54
pubmed: 23339170
Hypertension. 2016 Mar;67(3):630-9
pubmed: 26781277
Curr Hypertens Rep. 2006 May;8(2):144-52
pubmed: 16672148
Clin Exp Pharmacol Physiol. 2016 May;43(5):535-42
pubmed: 26876143
Am J Physiol Renal Physiol. 2015 Jun 15;308(12):F1379-85
pubmed: 25855512
Kidney Int. 1980 Aug;18(2):253-8
pubmed: 6255223
Lancet. 2010 Aug 21;376(9741):631-44
pubmed: 20598363
Am J Hypertens. 2001 Jun;14(6 Pt 2):98S-102S
pubmed: 11411772
Hypertension. 2005 Dec;46(6):1243-9
pubmed: 16230510
J Exp Med. 2014 Jan 13;211(1):165-79
pubmed: 24395887
Kidney Int. 2013 Nov;84(5):931-9
pubmed: 23823602
Hypertension. 2020 Jun;75(6):1363-1381
pubmed: 32248704
Cell Res. 2001 Sep;11(3):165-80
pubmed: 11642401
Br J Nutr. 2012 Mar;107(5):665-73
pubmed: 21787449
Acta Physiol Scand. 2000 Jan;168(1):65-71
pubmed: 10691781
Kidney Int. 1998 Dec;54(6):2056-63
pubmed: 9853271
Physiol Rev. 2005 Apr;85(2):571-633
pubmed: 15788706
Hypertension. 2002 May;39(5):1021-7
pubmed: 12019286
Med J Malaysia. 2006 Jun;61(2):173-80
pubmed: 16898308
Endocrinology. 2009 Sep;150(9):4316-25
pubmed: 19520788
Clin Cardiol. 1995 Jun;18(6 Suppl 3):III 29-34
pubmed: 7634561
Obstet Gynecol. 1998 Feb;91(2):196-202
pubmed: 9469275
BJOG. 2003 Mar;110(3):301-5
pubmed: 12628272
J Hum Hypertens. 2017 Jan;31(1):49-55
pubmed: 27030287
Hypertension. 2017 Aug;70(2):382-389
pubmed: 28652473
Obstet Gynecol Int. 2012;2012:658310
pubmed: 22203847
Philos Trans R Soc Lond B Biol Sci. 2015 Mar 5;370(1663):20140068
pubmed: 25602072
Vasc Health Risk Manag. 2011;7:467-74
pubmed: 21822394
Am J Hypertens. 2017 Nov 1;30(11):1053-1062
pubmed: 28472224
Hypertension. 1998 Jan;31(1 Pt 2):349-55
pubmed: 9453327
Hypertension. 2003 Dec;42(6):1177-82
pubmed: 14581297
N Engl J Med. 2008 Jul 3;359(1):61-73
pubmed: 18596274
Biochem Biophys Res Commun. 1999 Apr 29;258(1):194-8
pubmed: 10222259
Am J Physiol Regul Integr Comp Physiol. 2018 Apr 1;314(4):R499-R508
pubmed: 29212809
Biol Reprod. 2020 Mar 13;102(3):660-670
pubmed: 31711123
Hypertension. 2010 May;55(5):1239-45
pubmed: 20308605
Case Rep Pediatr. 2018 Jan 11;2018:5412138
pubmed: 29527375
Integr Blood Press Control. 2013 Nov 22;6:153-61
pubmed: 24379697
Biol Reprod. 2005 Mar;72(3):762-6
pubmed: 15564595
Hypertension. 2014 Sep;64(3):626-31
pubmed: 24935937
Biology (Basel). 2020 Jul 20;9(7):
pubmed: 32698476
Physiol Rev. 1990 Oct;70(4):921-61
pubmed: 2217559
Biochem Biophys Res Commun. 1997 Oct 20;239(2):633-7
pubmed: 9344883
Clin Sci (Lond). 2011 Oct;121(7):297-303
pubmed: 21542804
Hypertension. 2011 Feb;57(2):308-13
pubmed: 21189405
Med Sci Monit. 2000 May-Jun;6(3):523-9
pubmed: 11208365
J Renin Angiotensin Aldosterone Syst. 2016 Oct 19;17(4):
pubmed: 27765882
J Clin Invest. 1999 Apr;103(7):945-52
pubmed: 10194466
Early Hum Dev. 2011 Jun;87(6):407-14
pubmed: 21450421
Curr Pharm Des. 2013;19(17):2988-95
pubmed: 23176210
J Clin Invest. 1973 Nov;52(11):2682-9
pubmed: 4355997
Semin Nephrol. 2011 Jan;31(1):47-58
pubmed: 21266264
Am J Obstet Gynecol. 1993 Jan;168(1 Pt 1):268-74
pubmed: 8420338
Curr Opin Nephrol Hypertens. 2011 Mar;20(2):125-32
pubmed: 21245762
Nature. 2004 Jul 22;430(6998):419-21
pubmed: 15269759
Biol Reprod. 2018 Nov 1;99(5):1091-1099
pubmed: 29860295
Circ Res. 1999 Apr 30;84(8):876-82
pubmed: 10222333
Int Immunopharmacol. 2008 Feb;8(2):312-8
pubmed: 18182246
Mol Genet Genomic Med. 2020 Jan;8(1):e1019
pubmed: 31701677
Br J Pharmacol. 2003 Nov;140(5):987-95
pubmed: 14530222
Sci Rep. 2020 Sep 24;10(1):15590
pubmed: 32973289
Obstet Gynecol. 2013 Nov;122(5):1122-1131
pubmed: 24150027
Pharmacol Res Perspect. 2020 Oct;8(5):e00644
pubmed: 32815286
Hypertension. 2014 Aug;64(2):405-14
pubmed: 24842922
Circulation. 2014 Sep 16;130(12):1003-8
pubmed: 25223771
Mol Cell Endocrinol. 2001 Nov 26;184(1-2):95-102
pubmed: 11694345
Biol Reprod. 2014 Jul;91(1):6
pubmed: 24855104
Hypertension. 2001 Dec 1;38(6):1272-7
pubmed: 11751702
Reprod Biol Endocrinol. 2011 Aug 03;9:110
pubmed: 21812961
Obstet Gynecol. 1992 Dec;80(6):1000-6
pubmed: 1448242
J Clin Invest. 1999 Oct;104(7):925-35
pubmed: 10510333
Hypertension. 2012 Feb;59(2):291-9
pubmed: 22184324
Biomed Res Int. 2014;2014:982159
pubmed: 24959596