title: RGS2 squelches vascular Gi/o and Gq signaling to modulate myogenic tone and promote uterine blood flow.
abstract: Uterine artery blood flow (UABF) is critical to maintaining uterine perfusion in nonpregnant states and for uteroplacental delivery of nutrients and oxygen to the fetus during pregnancy. Impaired UABF is implicated in infertility and several pregnancy complications including fetal growth restriction, small for gestational age, and preeclampsia. The etiology of abnormal UABF is not known. Here, we determined whether deficiency or loss of RGS2, a GTPase-activating protein for Gq/11 and Gi/o class G proteins, affects UABF in nonpregnant mice. We used Doppler ultrasonography to assess UABF in wild type (WT), Rgs2 heterozygous (Rgs2+/-), and homozygous knockout (Rgs2-/-) mice. Video microscopy was used for ex vivo examination of uterine artery myogenic tone and fura-2 imaging for in vitro assessment of internal stores Ca(2+) release. We found that baseline UABF velocity was markedly decreased while impedance measured as resistive index (WT = 0.58 ± 0.04 vs. Rgs2-/- = 0.71 ± 0.03, P < 0.01) and pulsatile index (WT = 0.90 ± 0.06 vs. Rgs2-/- = 1.25 ± 0.11, P < 0.01) was increased in Rgs2-/- mice. Uterine artery tone was augmented in Rgs2+/- and Rgs2-/- mice, which was normalized to WT levels following Gi/o and Gq inactivation. Conversely, blockade of ryanodine receptors increased WT myogenic tone to RGS2 mutant levels. The data together indicate that RGS2 deficiency decreases UABF by increasing myogenic tone at least partly through prolonged G protein activation. Mutations that decrease vascular RGS2 expression may be a predisposition to decreased uterine blood flow. Targeting G protein signaling therefore might improve uterine and uteroplacental underperfusion disorders.
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Jie
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Owens
authors.affiliation: Department of Obstetrics & Gynecology, Drexel University College of Medicine, Philadelphia, Pennsylvania.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Plante
authors.affiliation: Jiangsu Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China.
authors.forename: Zhuyuan
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Chemistry, Washington University, St. Louis, Missouri.
authors.forename: Derek T
authors.initials: DT
authors.lastname: Rensing
authors.affiliation: Department of Chemistry, Washington University, St. Louis, Missouri.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Moeller
authors.affiliation: Department of Pharmacology & Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania patrick.osei-owusu@drexelmed.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Osei-Owusu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009129:Muscle Tonus / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D011247:Pregnancy; D020710:RGS Proteins / Q000378:metabolism*; D018608:Ultrasonography, Doppler; D055988:Uterine Artery / Q000378:metabolism*; D014599:Uterus / Q000098:blood supply*
chemical_list: D020710:RGS Proteins; C105345:Rgs2 protein, mouse; D019204:GTP-Binding Proteins
keywords: G protein signaling; RGS2; myogenic tone, calcium; uterine blood flow
references.citation: Physiol Rep. 2016 Feb;4(2):
references.pmid: 26811058
references.citation: Acta Physiol Scand. 1998 Dec;164(4):577-87
references.pmid: 9887980
references.citation: Clin Sci (Lond). 2009 Mar;116(5):391-9
references.pmid: 19175357
references.citation: J Hypertens. 2006 Jun;24(6):1115-24
references.pmid: 16685212
references.citation: Front Biosci. 2003 Jan 01;8:d46-54
references.pmid: 12456314
references.citation: Org Lett. 2015 May 1;17(9):2270-3
references.pmid: 25875152
references.citation: Cardiovasc Res. 2001 Mar;49(4):828-37
references.pmid: 11230983
references.citation: Hypertension. 2013 Mar;61(3):655-61
references.pmid: 23339167
references.citation: Sci Transl Med. 2015 Jun 3;7(290):290ra88
references.pmid: 26041705
references.citation: Hypertension. 2010 Apr;55(4):983-9
references.pmid: 20194294
references.citation: J Vasc Res. 2000 Nov-Dec;37(6):556-67
references.pmid: 11146410
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12272-7
references.pmid: 11027316
references.citation: Nutr Metab (Lond). 2012 Mar 16;9(1):18
references.pmid: 22424473
references.citation: Nature. 1996 Sep 12;383(6596):172-5
references.pmid: 8774882
references.citation: PLoS One. 2015 Jul 20;10(7):e0132594
references.pmid: 26193676
references.citation: J Cell Mol Med. 2008 Dec;12(6A):2165-80
references.pmid: 19120701
references.citation: Ultrasound Med Biol. 2014 Feb;40(2):351-60
references.pmid: 24342911
references.citation: Circ Res. 2009 Feb 27;104(4):531-40
references.pmid: 19131646
references.citation: Cardiovasc Res. 2012 Jul 15;95(2):223-32
references.pmid: 22637750
references.citation: Hum Reprod. 1998 Jun;13(6):1669-73
references.pmid: 9688410
references.citation: Int J Biochem Cell Biol. 2012 Sep;44(9):1505-10
references.pmid: 22677491
references.citation: Cell Calcium. 2003 Sep;34(3):211-29
references.pmid: 12887969
references.citation: BMC Med Genet. 2014 Mar 05;15:28
references.pmid: 24593135
references.citation: Nat Med. 2008 Jan;14(1):64-8
references.pmid: 18084302
references.citation: Science. 1995 Oct 27;270(5236):633-7
references.pmid: 7570021
references.citation: Methods Enzymol. 2004;390:65-82
references.pmid: 15488171
references.citation: Cell Signal. 2010 Sep;22(9):1274-81
references.pmid: 20363320
references.citation: Fertil Steril. 1995 Jan;63(1):101-8
references.pmid: 7805896
references.citation: J Clin Invest. 2003 Feb;111(4):445-52
references.pmid: 12588882
references.citation: Physiol Rev. 1999 Apr;79(2):387-423
references.pmid: 10221985
references.citation: Physiology (Bethesda). 2009 Feb;24:58-71
references.pmid: 19196652
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14389-93
references.pmid: 9405622
references.citation: Curr Opin Pharmacol. 2011 Apr;11(2):112-6
references.pmid: 21147033
references.citation: J Cell Biol. 2009 Sep 7;186(5):755-65
references.pmid: 19736320
references.citation: Circ Res. 2005 Mar 4;96(4):401-11
references.pmid: 15746448
references.citation: Nat Med. 2003 Dec;9(12):1506-12
references.pmid: 14608379
references.citation: EMBO J. 2008 Dec 3;27(23):3092-103
references.pmid: 18987636
references.citation: J Physiol. 1998 Apr 1;508 ( Pt 1):211-21
references.pmid: 9490841
references.citation: Annu Rev Biochem. 2000;69:795-827
references.pmid: 10966476
references.citation: J Biol Chem. 2007 Oct 26;282(43):31656-65
references.pmid: 17681944
references.citation: Mol Pharmacol. 2008 Apr;73(4):1037-43
references.pmid: 18230714
references.citation: J Biol Chem. 2012 Apr 6;287(15):12541-9
references.pmid: 22354966
references.citation: Recept Channels. 2003;9(3):135-47
references.pmid: 12775336
references.citation: Am J Obstet Gynecol. 1990 Jan;162(1):121-5
references.pmid: 2301480
references.citation: Fertil Steril. 1996 Jul;66(1):130-4
references.pmid: 8752624
references.citation: Prog Mol Biol Transl Sci. 2009;86:205-27
references.pmid: 20374717