Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia.
Relaxin is an approximately 6-kilodalton peptide hormone secreted by the corpus luteum, and circulates in the maternal blood during pregnancy. Relaxin administration to awake, chronically instrumented, nonpregnant rats mimics the vasodilatory phenomena of pregnancy. Furthermore, immunoneutralization of relaxin or its elimination from the circulation during midterm pregnancy in awake rats prevents maternal systemic and renal vasodilation, and the increase in global arterial compliance. Human investigation, albeit limited through 2010, also reveals vasodilatory effects of relaxin in the nonpregnant condition and observations consistent with a role for relaxin in gestational renal hyperfiltration. Evidence suggests that the vasodilatory responses of relaxin are mediated by its major receptor, the relaxin/insulin-like family peptide 1 receptor, RFXP1. The molecular mechanisms of relaxin vasodilation depend on the duration of hormone exposure (ie, there are rapid and sustained vasodilatory responses). Newly emerging data support the role of Gα(i/o) protein coupling to phosphatidylinositol-3 kinase/Akt (protein kinase B)-dependent phosphorylation and activation of endothelial nitric oxide synthase in the rapid vasodilatory responses of relaxin. Sustained vasodilatory responses critically depend on vascular endothelial and placental growth factors, and increases in arterial gelatinase(s) activity. Gelatinases hydrolyze big endothelin (ET) at a gly-leu bond to form ET(1-32), which activates the endothelial ET(B)/nitric oxide vasodilatory pathway. Although the relevance of relaxin biology to preeclampsia is largely speculative at this time, there are potential tantalizing links that are discussed in the context of our current understanding of the etiology and pathophysiology of the disease.
Department of Physiology and Functional Genomics, University of Florida College of Medicine, 1600 SW Archer Road, Gainesville, FL 32610, USA. kpconrad@ufl.edu
Kirk P
KP
Conrad
D000222:Adaptation, Physiological; D000818:Animals; D005260:Female; D006439:Hemodynamics; D006801:Humans; D023421:Models, Animal; D011225:Pre-Eclampsia / Q000378:metabolism / Q000503:physiopathology*; D011247:Pregnancy / Q000378:metabolism / Q000502:physiology*; D012065:Relaxin / Q000378:metabolism / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
D012065:Relaxin
Semin Cell Biol. 1993 Jun;4(3):183-8
8347835
Am J Physiol. 1992 Dec;263(6 Pt 2):H1911-8
1481914
Am J Physiol Heart Circ Physiol. 2000 May;278(5):H1585-8
10775137
J Soc Gynecol Investig. 2004 Jul;11(5):280-8
15219881
Am J Physiol. 1999 Jul;277(1 Pt 2):F48-57
10409297
Am J Physiol. 1999 Aug;277(2):H848-54
10444514
Endocrine. 2007 Dec;32(3):303-10
18236174
J Clin Invest. 2001 Jun;107(11):1469-75
11390429
Endocr Rev. 2004 Apr;25(2):205-34
15082520
Ann N Y Acad Sci. 1994 Sep 6;732:315-23
7978801
Obstet Gynecol. 1982 Feb;59(2):167-70
7078861
Am J Obstet Gynecol. 2002 Nov;187(5):1416-23
12439541
N Engl J Med. 2004 Feb 12;350(7):672-83
14764923
J Clin Invest. 1955 Oct;34(10):1524-36
13263433
Arthritis Rheum. 2009 Apr;60(4):1102-11
19333948
Am J Physiol Regul Integr Comp Physiol. 2000 Oct;279(4):R1298-304
11003996
Endocrinology. 1967 Aug;81(2):375-85
4952013
J Soc Gynecol Investig. 2004 Oct;11(7):438-48
15458740
Adv Exp Med Biol. 2007;612:34-48
18161480
Placenta. 2010 Mar;31 Suppl:S93-8
20060584
Am J Physiol. 1996 May;270(5 Pt 2):H1779-84
8928886
Am J Physiol. 1997 Feb;272(2 Pt 2):R441-63
9124465
Semin Reprod Med. 2008 Sep;26(5):423-35
18825610
FASEB J. 2006 Nov;20(13):2352-62
17077312
Hypertension. 1997 Sep;30(3 Pt 2):580-4
9322985
J Clin Invest. 2006 Oct;116(10):2643-52
16998586
Semin Reprod Med. 2007 Nov;25(6):445-53
17960529
Nat Biotechnol. 1999 Aug;17(8):768-74
10429241
Placenta. 2000 Jan;21(1):23-31
10692247
Annu Rev Physiol. 2002;64:749-74
11826287
J Appl Physiol (1985). 2006 Jun;100(6):1955-63
16484357
Kidney Int. 1996 Oct;50(4):1132-8
8887270
J Biol Chem. 2006 Nov 17;281(46):34942-54
16963451
J Clin Invest. 1986 Jan;77(1):236-45
3944253
Am J Physiol. 1997 Feb;272(2 Pt 2):H748-52
9124434
Kidney Int. 1984 Jul;26(1):24-9
6332938
Clin Exp Pharmacol Physiol. 1999 Mar;26(3):269-71
10081626
Endocrinology. 2004 Jul;145(7):3289-96
15198972
Circulation. 2002 Jul 16;106(3):292-5
12119241
Placenta. 2009 Jun;30(6):473-82
19375795
Trends Endocrinol Metab. 2003 Jul;14(5):207-13
12826326
Hum Reprod. 1999 Mar;14(3):800-6
10221717
Am J Obstet Gynecol. 1997 May;176(5):1069-76
9166170
Adv Exp Med Biol. 2007;612:65-87
18161482
J Pharmacol Exp Ther. 2005 Jan;312(1):83-95
15367576
Fertil Steril. 2006 Jul;86(1):253-5
16730722
J Clin Endocrinol Metab. 1978 Nov;47(5):1106-10
263340
Circulation. 1997 May 20;95(10):2407-15
9170404
Endocrinology. 2006 Nov;147(11):5126-31
16873529
Endocrinology. 2005 Jun;146(6):2791-7
15761039
J Clin Invest. 1999 Apr;103(7):945-52
10194466
Am J Pathol. 1999 Jul;155(1):293-301
10393861
Endocrinology. 2007 Jan;148(1):189-97
17053025
Mol Cell Endocrinol. 2003 Mar 28;201(1-2):63-73
12706295
Br J Pharmacol. 1995 Sep;116(1):1589-94
8564223
Am J Physiol. 1997 Nov;273(5):F777-82
9374841
Life Sci. 1985 Oct 7;37(14):1351-7
4046737
Hypertens Pregnancy. 2001;20(2):185-94
12044329
Am J Physiol Regul Integr Comp Physiol. 2004 Aug;287(2):R250-61
15271674
J Appl Physiol (1985). 2003 Oct;95(4):1509-14
12819218
J Clin Endocrinol Metab. 1977 Mar;44(3):590-4
190264
J Clin Endocrinol Metab. 1990 Jun;70(6):1771-3
2347909
J Card Fail. 2009 Apr;15(3):182-90
19327619
Circ Res. 2003 Jan 10;92(1):32-40
12522118
J Investig Med. 1996 Oct;44(8):447-53
8952225
Am J Physiol Regul Integr Comp Physiol. 2007 Aug;293(2):R766-74
17507435
J Reprod Immunol. 2007 Dec;76(1-2):61-7
17482271
Am J Kidney Dis. 1987 Apr;9(4):253-9
3554994
J Clin Invest. 1995 Jul;96(1):482-90
7542284
J Anat. 2009 Jul;215(1):21-6
19215319
J Appl Physiol (1985). 2005 Mar;98(3):1013-20
15489259
Int J Dev Biol. 2010;54(2-3):269-80
19876833
Am J Physiol Renal Physiol. 2001 Apr;280(4):F592-8
11249850
Eur J Obstet Gynecol Reprod Biol. 2009 Nov;147(1):41-5
19695764
Ann N Y Acad Sci. 2009 Apr;1160:130-5
19416173
J Vasc Res. 2008;45(4):350-6
18332633
Placenta. 2009 Mar;30 Suppl A:S38-42
19138798
Am J Physiol Regul Integr Comp Physiol. 2002 Aug;283(2):R349-55
12121847
Science. 2005 Jun 10;308(5728):1592-4
15947178
Am J Physiol. 1989 Oct;257(4 Pt 2):R847-53
2552845
Am J Obstet Gynecol. 1996 Feb;174(2):573-7
8623787
Circ Res. 1996 Dec;79(6):1161-6
8943954
Ann N Y Acad Sci. 2009 Apr;1160:60-6
19416160
Mol Hum Reprod. 2004 May;10(5):331-7
15044600
J Clin Invest. 1999 Feb;103(4):525-33
10021461
J Clin Endocrinol Metab. 2001 Jun;86(6):2505-12
11397847
Placenta. 2005 Aug;26(7):563-73
15993706
Hypertension. 1995 Apr;25(4 Pt 1):631-6
7721408
Am J Obstet Gynecol. 1989 Sep;161(3):618-22
2782343
Nature. 1987 Jun 11-17;327(6122):524-6
3495737
J Am Soc Nephrol. 2006 May;17(5):1325-33
16597680
Proc Soc Exp Biol Med. 1989 Mar;190(3):254-9
2922410
Obstet Gynecol. 1994 Sep;84(3):338-42
8058227
Am J Physiol Regul Integr Comp Physiol. 2005 Jan;288(1):R322-8
15388493
Circ Res. 2003 Dec 12;93(12):1249-57
14593002
Am J Physiol Regul Integr Comp Physiol. 2001 Jan;280(1):R1-7
11124127
J Am Soc Nephrol. 2006 Nov;17(11):3192-7
17035617
Hypertension. 2005 Oct;46(4):745-50
16172427
Hypertension. 1999 Jan;33(1 Pt 2):435-9
9931143
Placenta. 2004 Nov;25(10):763-9
15451190
Biol Reprod. 1998 Oct;59(4):991-9
9746753
Am J Obstet Gynecol. 2005 Jul;193(1):185-91
16021077
Ann N Y Acad Sci. 2009 Apr;1160:304-12
19416209
Endocrinology. 2008 May;149(5):2072-9
18218691
J Clin Invest. 2003 Mar;111(5):649-58
12618519
Hypertension. 2009 Jun;53(6):952-8
19398652
Am J Physiol. 1995 Jul;269(1 Pt 2):H365-74
7631869
Ther Adv Cardiovasc Dis. 2008 Aug;2(4):261-75
19124426
Am J Physiol. 1999 May;276(5):F767-76
10330059
Placenta. 1997 Nov;18(8):657-65
9364601
Circ Res. 1999 Nov 12;85(10):906-11
10559137
Reprod Biol Endocrinol. 2004 Jun 16;2:36
15200675
Front Biosci. 2007 Jan 01;12:2403-11
17127250
Biol Reprod. 2001 Feb;64(2):499-506
11159352
FASEB J. 1993 Apr 1;7(6):566-71
7682524
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4685-9
15070778
Placenta. 2009 Jan;30(1):15-24
19027158