title: The Expanding Complexity of Estrogen Receptor Signaling in the Cardiovascular System.
abstract: Estrogen has important effects on cardiovascular function including regulation of vascular function, blood pressure, endothelial relaxation, and the development of hypertrophy and cardioprotection. However, the mechanisms by which estrogen mediates these effects are still poorly understood. As detailed in this review, estrogen can regulate transcription by binding to 2 nuclear receptors, ERα and ERβ, which differentially regulate gene transcription. ERα and ERβ regulation of gene transcription is further modulated by tissue-specific coactivators and corepressors. Estrogen can bind to ERα and ERβ localized at the plasma membrane as well as G-protein-coupled estrogen receptor to initiate membrane delimited signaling, which enhances kinase signaling pathways that can have acute and long-term effects. The kinase signaling pathways can also mediate transcriptional changes and can synergize with the ER to regulate cell function. This review will summarize the beneficial effects of estrogen in protecting the cardiovascular system through ER-dependent mechanisms with an emphasis on the role of the recently described ER membrane signaling mechanisms.
authors.affiliation: From the Systems Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD. sara.menazza@nih.gov.
authors.forename: Sara
authors.initials: S
authors.lastname: Menazza
authors.affiliation: From the Systems Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Murphy
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen
keywords: MAP kinase signaling pathways; PI3 kinases; estrogens; receptors, G-protein–coupled; signal transduction
references.citation: J Biol Chem. 2001 Oct 5;276(40):36865-8
references.pmid: 11459854
references.citation: Mol Biol Cell. 2013 Dec;24(24):3805-18
references.pmid: 24152730
references.citation: Am J Physiol Heart Circ Physiol. 2005 Nov;289(5):H2039-47
references.pmid: 15994857
references.citation: Mol Cell Endocrinol. 2014 Feb 15;382(2):909-14
references.pmid: 24275180
references.citation: J Clin Endocrinol Metab. 2011 Jan;96(1):220-8
references.pmid: 20962025
references.citation: Mol Endocrinol. 2003 Feb;17(2):203-8
references.pmid: 12554748
references.citation: Am J Physiol Heart Circ Physiol. 2010 Jan;298(1):H16-23
references.pmid: 19880667
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17126-31
references.pmid: 15569929
references.citation: Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1524-30
references.pmid: 16627800
references.citation: Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):E283-90
references.pmid: 24371309
references.citation: J Biol Chem. 2011 Apr 8;286(14):12640-9
references.pmid: 21285458
references.citation: PLoS One. 2015 Sep 30;10(9):e0139608
references.pmid: 26422690
references.citation: Circ Res. 2002 May 31;90(10):1087-92
references.pmid: 12039798
references.citation: Am J Physiol Heart Circ Physiol. 2010 Mar;298(3):H1055-61
references.pmid: 20061543
references.citation: J Biol Chem. 2005 May 20;280(20):19704-10
references.pmid: 15764600
references.citation: Mol Endocrinol. 2007 Jun;21(6):1370-80
references.pmid: 17405905
references.citation: Science. 2002 Jan 18;295(5554):505-8
references.pmid: 11799247
references.citation: Mol Cell Biol. 2004 Jun;24(11):4605-12
references.pmid: 15143157
references.citation: Mol Endocrinol. 2008 Sep;22(9):2116-27
references.pmid: 18617595
references.citation: FEBS Lett. 1996 Aug 19;392(1):49-53
references.pmid: 8769313
references.citation: J Clin Endocrinol Metab. 2009 Sep;94(9):3513-20
references.pmid: 19509105
references.citation: J Biol Chem. 1995 Jul 14;270(28):16483-6
references.pmid: 7622446
references.citation: Endocrinology. 1997 Nov;138(11):4613-21
references.pmid: 9348186
references.citation: Cardiovasc Res. 2005 Sep 1;67(4):604-12
references.pmid: 15950203
references.citation: J Biol Chem. 2007 Aug 3;282(31):22278-88
references.pmid: 17535799
references.citation: Surgery. 2010 Aug;148(2):436-43
references.pmid: 20434187
references.citation: Nature. 1977 Jan 6;265(5589):69-72
references.pmid: 834244
references.citation: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2421-7
references.pmid: 18441199
references.citation: Biochem Biophys Res Commun. 1998 Oct 9;251(1):17-21
references.pmid: 9790900
references.citation: Endocrinology. 2007 Nov;148(11):5295-304
references.pmid: 17673517
references.citation: Biochem Biophys Res Commun. 2006 Aug 4;346(3):904-10
references.pmid: 16780796
references.citation: J Mol Histol. 2013 Apr;44(2):221-9
references.pmid: 23271141
references.citation: Cardiovasc Res. 2014 Jun 1;102(3):418-28
references.pmid: 24654233
references.citation: Mol Biol Cell. 2005 Jan;16(1):231-7
references.pmid: 15496458
references.citation: Steroids. 2004 Aug;69(8-9):537-42
references.pmid: 15288766
references.citation: Dev Cell. 2014 May 27;29(4):482-90
references.pmid: 24871949
references.citation: Circulation. 2005 May 10;111(18):2282-90
references.pmid: 15867180
references.citation: Circulation. 2012 Oct 16;126(16):1993-2004
references.pmid: 22997253
references.citation: Cardiovasc Res. 1999 Aug 15;43(3):788-97
references.pmid: 10690351
references.citation: Biochem Biophys Res Commun. 2002 Jun 28;294(5):926-33
references.pmid: 12074565
references.citation: Eur J Pharmacol. 2013 Jan 15;699(1-3):74-80
references.pmid: 23219795
references.citation: J Physiol Biochem. 2014 Mar;70(1):151-62
references.pmid: 24037795
references.citation: Science. 2005 Mar 11;307(5715):1625-30
references.pmid: 15705806
references.citation: Mol Endocrinol. 2003 Oct;17(10):2070-83
references.pmid: 12893882
references.citation: Circulation. 2003 Jan 7;107(1):120-6
references.pmid: 12515753
references.citation: Nature. 2014 May 15;509(7500):282-3
references.pmid: 24834516
references.citation: Pharmacology. 2010;86(1):58-64
references.pmid: 20639684
references.citation: Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1806-13
references.pmid: 19717735
references.citation: J Cardiovasc Pharmacol. 2011 May;57(5):598-603
references.pmid: 21326105
references.citation: Am J Physiol Endocrinol Metab. 2004 Jun;286(6):E1011-22
references.pmid: 14736707
references.citation: Biochem Biophys Res Commun. 1999 Sep 16;263(1):257-62
references.pmid: 10486286
references.citation: Hypertension. 2006 Jun;47(6):1019-26
references.pmid: 16651458
references.citation: Am J Physiol Heart Circ Physiol. 2005 Feb;288(2):H469-76
references.pmid: 15374829
references.citation: Trends Cardiovasc Med. 2006 Apr;16(3):69-75
references.pmid: 16546686
references.citation: J Comp Neurol. 2009 Feb 10;512(5):688-701
references.pmid: 19051266
references.citation: Mol Endocrinol. 2006 Sep;20(9):1996-2009
references.pmid: 16645038
references.citation: J Mol Endocrinol. 2008 Apr;40(4):173-84
references.pmid: 18372406
references.citation: Biochim Biophys Acta. 1998 Mar 5;1406(2):169-74
references.pmid: 9573355
references.citation: Endocr Rev. 2002 Oct;23(5):665-86
references.pmid: 12372846
references.citation: PLoS One. 2013 Jun 19;8(6):e64771
references.pmid: 23840305
references.citation: J Biol Chem. 2001 Oct 5;276(40):36869-72
references.pmid: 11459850
references.citation: Science. 2005 Jun 10;308(5728):1583-7
references.pmid: 15947175
references.citation: Arterioscler Thromb Vasc Biol. 2010 Dec;30(12):2562-7
references.pmid: 20847304
references.citation: Mol Cell. 2008 Jul 25;31(2):212-21
references.pmid: 18657504
references.citation: J Endocrinol. 2008 Jun;197(3):493-501
references.pmid: 18492815
references.citation: Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1837-43
references.pmid: 23744991
references.citation: Circ Res. 2002 Nov 1;91(9):814-20
references.pmid: 12411396
references.citation: Mol Endocrinol. 2000 Oct;14(10):1649-60
references.pmid: 11043579
references.citation: Biochem Biophys Res Commun. 2004 Apr 9;316(3):878-83
references.pmid: 15033483
references.citation: Circ Res. 2009 Feb 13;104(3):288-91
references.pmid: 19179659
references.citation: Acta Pharmacol Sin. 2011 Apr;32(4):433-40
references.pmid: 21399653
references.citation: PLoS One. 2013 Aug 05;8(8):e70926
references.pmid: 23940668
references.citation: J Clin Invest. 2014 Jun;124(6):2375-7
references.pmid: 24837428
references.citation: Mol Pharmacol. 2011 Mar;79(3):400-10
references.pmid: 21149639
references.citation: Pathophysiology. 2008 Jun;15(1):49-67
references.pmid: 18434105
references.citation: J Endocrinol. 2001 May;169(2):241-7
references.pmid: 11312141
references.citation: Endocrinology. 2013 Jun;154(6):2101-13
references.pmid: 23515288
references.citation: Circulation. 2000 Apr 4;101(13):1594-7
references.pmid: 10747354
references.citation: J Am Coll Cardiol. 2012 Jan 24;59(4):410-7
references.pmid: 22261164
references.citation: EMBO J. 2001 Nov 1;20(21):6050-9
references.pmid: 11689445
references.citation: N Engl J Med. 2003 Aug 7;349(6):535-45
references.pmid: 12904518
references.citation: Circ Res. 2010 Jun 11;106(11):1681-91
references.pmid: 20413785
references.citation: Physiol Genomics. 2011 Sep 22;43(18):1065-73
references.pmid: 21750230
references.citation: Cardiovasc Res. 1999 Sep;43(4):985-91
references.pmid: 10615426
references.citation: Redox Biol. 2014;3:88-99
references.pmid: 25462070
references.citation: Circulation. 2000 Apr 18;101(15):1792-8
references.pmid: 10769279
references.citation: JAMA. 2002 Jul 3;288(1):49-57
references.pmid: 12090862
references.citation: JAMA. 1991 Apr 10;265(14):1861-7
references.pmid: 2005736
references.citation: J Biol Chem. 2003 Feb 14;278(7):4639-45
references.pmid: 12466266
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12626-30
references.pmid: 8901633
references.citation: Mol Cell Biol. 2003 Mar;23(5):1633-46
references.pmid: 12588983
references.citation: Nat Chem Biol. 2006 Apr;2(4):207-12
references.pmid: 16520733
references.citation: J Vasc Res. 2011;48(4):327-35
references.pmid: 21273787
references.citation: Endocrinology. 2005 Feb;146(2):624-32
references.pmid: 15539556
references.citation: Mol Endocrinol. 2004 Dec;18(12):2854-65
references.pmid: 15231873
references.citation: J Mol Cell Cardiol. 2007 Apr;42(4):769-80
references.pmid: 17362982
references.citation: BMC Genomics. 2015 May 09;16:367
references.pmid: 25956916
references.citation: Mol Cell Biol. 2010 Jul;30(13):3249-61
references.pmid: 20439495
references.citation: Physiol Genomics. 2008 Jan 17;32(2):254-63
references.pmid: 17986523
references.citation: J Biol Chem. 2005 Jul 15;280(28):26339-48
references.pmid: 15899894
references.citation: J Biol Chem. 2003 Oct 31;278(44):43363-72
references.pmid: 12917431
references.citation: J Biol Chem. 2001 Apr 27;276(17):13615-21
references.pmid: 11278408
references.citation: Circ Res. 2000 Nov 24;87(11):E44-52
references.pmid: 11090554
references.citation: FEBS Lett. 2001 Aug 3;502(3):103-8
references.pmid: 11583108
references.citation: Mol Endocrinol. 2013 Jan;27(1):2-11
references.pmid: 23242705
references.citation: Nature. 2000 Sep 28;407(6803):538-41
references.pmid: 11029009
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4807-12
references.pmid: 12682286
references.citation: J Clin Invest. 1998 Jul 1;102(1):176-83
references.pmid: 9649571
references.citation: Hypertension. 2007 Jun;49(6):1358-63
references.pmid: 17452498
references.citation: J Clin Invest. 1996 Jul 1;98(1):36-42
references.pmid: 8690801
references.citation: Circ Res. 2003 Jul 25;93(2):170-7
references.pmid: 12816884
references.citation: J Cell Sci Ther. 2014 Jan 30;5(1):153
references.pmid: 24977106
references.citation: Am J Physiol Heart Circ Physiol. 2003 Aug;285(2):H687-92
references.pmid: 12714326
references.citation: J Biol Chem. 2003 Jan 24;278(4):2118-23
references.pmid: 12431978
references.citation: Mol Pharmacol. 2005 Jan;67(1):105-13
references.pmid: 15496504
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1605-8
references.pmid: 16423895
references.citation: Mol Cell Endocrinol. 2014 May 25;389(1-2):71-83
references.pmid: 24530924
references.citation: Mol Biol Cell. 2002 Oct;13(10):3720-9
references.pmid: 12388769
references.citation: Mol Endocrinol. 2007 Jun;21(6):1281-96
references.pmid: 17374850
references.citation: J Biol Chem. 2011 Jun 24;286(25):22441-55
references.pmid: 21540189
references.citation: Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1933-8
references.pmid: 24449868
references.citation: Mol Endocrinol. 2003 Sep;17(9):1844-55
references.pmid: 12829806
references.citation: Vascul Pharmacol. 2011 Jul-Sep;55(1-3):17-25
references.pmid: 21742056
references.citation: PLoS One. 2010 Nov 03;5(11):e15433
references.pmid: 21082029
references.citation: J Clin Invest. 2010 Jul;120(7):2319-30
references.pmid: 20577047
references.citation: Am J Cardiol. 2002 Jul 3;90(1A):3F-6F
references.pmid: 12106632
references.citation: J Clin Invest. 2014 Jun;124(6):2464-71
references.pmid: 24837433
references.citation: Hypertension. 2004 Feb;43(2):405-12
references.pmid: 14699001
references.citation: Mol Cell Endocrinol. 2015 Dec 15;418 Pt 3:273-97
references.pmid: 25659536
references.citation: Endocrinology. 2008 Jul;149(7):3361-9
references.pmid: 18372323
references.citation: J Am Coll Cardiol. 1995 Sep;26(3):807-14
references.pmid: 7642876
references.citation: Endocrinology. 2011 Dec;152(12 ):4537-49
references.pmid: 21990315
references.citation: J Endocrinol. 2008 Nov;199(2):267-73
references.pmid: 18753331
references.citation: Circ Res. 2000 Nov 24;87(11):956-60
references.pmid: 11090536
references.citation: Endocrinology. 2007 Jul;148(7):3236-45
references.pmid: 17379646
references.citation: Science. 2002 Mar 29;295(5564):2465-8
references.pmid: 11923541
references.citation: Am J Physiol Endocrinol Metab. 2011 Nov;301(5):E882-8
references.pmid: 21791623
references.citation: JAMA. 2013 Oct 2;310(13):1353-68
references.pmid: 24084921
references.citation: Circ Res. 2015 Oct 9;117(9):770-8
references.pmid: 26316608
references.citation: PLoS One. 2013 Dec 23;8(12):e84320
references.pmid: 24376801
references.citation: Physiol Rev. 2004 Jul;84(3):767-801
references.pmid: 15269336
references.citation: J Biol Chem. 2005 Mar 4;280(9):7460-8
references.pmid: 15615701
references.citation: Arterioscler Thromb Vasc Biol. 2003 Feb 1;23(2):198-203
references.pmid: 12588759
references.citation: J Gen Physiol. 1997 Aug;110(2):135-40
references.pmid: 9236206
references.citation: J Clin Invest. 1999 Feb;103(3):401-6
references.pmid: 9927501
references.citation: Endocrinology. 2009 Aug;150(8):3753-8
references.pmid: 19372194
references.citation: Circ Res. 2000 Oct 13;87(8):677-82
references.pmid: 11029403
references.citation: J Cardiovasc Pharmacol. 2000 Aug;36(2):196-202
references.pmid: 10942161
references.citation: Endocrinology. 2002 Mar;143(3):930-40
references.pmid: 11861515
references.citation: Pulm Circ. 2015 Mar;5(1):63-72
references.pmid: 25992271
references.citation: Cardiovasc Res. 1999 Aug 15;43(3):666-74
references.pmid: 10690338
references.citation: Circulation. 2000 Oct 10;102(15):1828-33
references.pmid: 11023939
references.citation: BMC Med Genomics. 2013 Jun 11;6:21
references.pmid: 23758675
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2205-10
references.pmid: 11854517
references.citation: Mol Endocrinol. 2002 May;16(5):938-46
references.pmid: 11981029
references.citation: Br J Pharmacol. 2000 Feb;129(3):555-65
references.pmid: 10711355
references.citation: Am J Physiol. 1997 Jul;273(1 Pt 1):L119-26
references.pmid: 9252548
references.citation: J Mol Cell Cardiol. 2004 Nov;37(5):921-9
references.pmid: 15522269
references.citation: Circ Res. 2009 Aug 14;105(4):343-52
references.pmid: 19608983
references.citation: Genomics. 1998 Jan 15;47(2):310-3
references.pmid: 9479505
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16468-73
references.pmid: 17921256
references.citation: J Pharmacol Exp Ther. 2009 Jun;329(3):850-5
references.pmid: 19293389
references.citation: PLoS One. 2014 Jul 07;9(7):e101900
references.pmid: 25000186
references.citation: Nat Med. 1997 May;3(5):545-8
references.pmid: 9142124
references.citation: Circulation. 2001 Jan 16;103(2):258-62
references.pmid: 11208686
references.citation: Mol Endocrinol. 2006 Mar;20(3):491-502
references.pmid: 16306086