Relaxin mediates uterine artery compliance during pregnancy and increases uterine blood flow

FASEB Journal

Volumn 26, Issue 10, 2012, Pages 4035-4044

  Vodstrcil, Lenka A ^a   Tare, Marianne ^b   Novak, Jacqueline ^c   Dragomir, Nicoleta ^a,f   Ramirez, Rolando J ^d   Wlodek, Mary E ^a   Conrad, Kirk P ^e   Parry, Laura J ^a  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b MONASH UNIVERSITY   (Australia)

^c WALSH UNIVERSITY   (United States)

^d UNIVERSITY OF AKRON   (United States)

^e UNIVERSITY OF FLORIDA   (United States)

^f VICTORIA UNIVERSITY   (Australia)

Author keywords

Extracellular matrix; Preeclampsia; RXFP1; Vascular smooth muscle

Indexed keywords

ALPHA SMOOTH MUSCLE ACTIN; HORMONE ANTIBODY; HORMONE RECEPTOR; RELAXIN; RELAXIN ANTIBODY; RELAXIN INSULIN LIKE FAMILY PEPTIDE RECEPTOR 1; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTERIAL STIFFNESS; ARTERIAL WALL THICKNESS; ARTERY COMPLIANCE; ARTICLE; BLOOD FLOW VELOCITY; CONTROLLED STUDY; ENDOTHELIUM CELL; ESTRUS; FEMALE; HORMONE ACTION; HORMONE RECEPTOR INTERACTION; NONHUMAN; PREGNANCY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN LOCALIZATION; RAT; SMOOTH MUSCLE FIBER; TISSUE STRUCTURE; TUNICA MEDIA; UTERINE ARTERY; UTERUS BLOOD FLOW; VASCULAR SMOOTH MUSCLE;

ANIMALS; ANTIBODIES, NEUTRALIZING; EXTRACELLULAR MATRIX; FEMALE; FLUORESCENT ANTIBODY TECHNIQUE; HUMANS; IMMUNOHISTOCHEMISTRY; MUSCLE, SMOOTH, VASCULAR; PREGNANCY; PREGNANCY, ANIMAL; RATS; RATS, INBRED WKY; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, PEPTIDE; RELAXIN; UTERINE ARTERY; UTERUS;

RATTUS;

EID: 84868128680     PISSN: None     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.12-210567     Document Type: Article

References (50)

1. Kelly, B., Stone, S., and Poston, L. (1999) Cardiovascular adaptation to pregnancy: the role of altered vascular structure. Fetal Matern. Med. Rev. 11, 105-116
2. Osol, G., and Mandala, M. (2009) Maternal uterine vascular remodeling during pregnancy. Physiology 24, 58-71
3. Gagnon, R. (2003) Placental insufficiency and its consequences. Eur. J. Obstet. Gyn. Reprod. Biol. 110, S99-S107
4. Granger, J. P., Alexander, B. T., Llinas, M. T., Bennett, W. A., and Khalil, R. A. (2002) Pathophysiology of preeclampsia: linking placental ischemia/hypoxia with microvascular dysfunction. Microcirculation 9, 147-160
5. Roberts, J. M., and Gammill, H. S. (2005) Preeclampsia: recent insights. Hypertension 46, 1243-1249
6. Griendling, K. K., Fuller, E. O., and Cox, R. H. (1985) Pregnancy- induced changes in sheep uterine and carotid arteries. Am. J. Physiol. 248, H658-H665
7. Bird, I. M., Zhang, L., and Magness, R. R. (2003) Possible mechanisms underlying pregnancy-induced changes in uterine artery endothelial function. Am. J. Physiol. 284, R245-R258
8. Van der Heijden, O. W., Essers, Y. P., Fazzi, G., Peeters, L. L., De Mey, J. G., and van Eys, G. J. (2005) Uterine artery remodeling and reproductive performance are impaired in endothelial nitric oxide synthase-deficient mice. Biol. Reprod. 72, 1161-1168
9. Van der Heijden, O. W., Essers, Y. P., Spaanderman, M. E., De Mey, J. G., van Eys, G. J., and Peeters, L. L. (2005) Uterine artery remodeling in pseudopregnancy is comparable to that in early pregnancy. Biol. Reprod. 73, 1289-1293
10. Osol, G., and Cipolla, M. (1993) Interaction of myogenic and adrenergic mechanisms in isolated, pressurized uterine radial arteries from late-pregnant and nonpregnant rats. Am. J. Obstet. Gynecol. 168, 697-705
11. Cipolla, M., and Osol, G. (1994) Hypertrophic and hyperplastic effects of pregnancy on the rat uterine arterial wall. Am. J. Obstet. Gynecol. 171, 805-811
12. Cipolla, M. J., Binder, N. D., and Osol, G. (1997) Myoendometrial versus placental uterine arteries: structural, mechanical, and functional differences in late-pregnant rabbits. Am. J. Obstet. Gynecol. 177, 215-221
13. Keyes, L. E., Moore, L. G., Walchak, S. J., and Dempsey, E. C. (1996) Pregnancy-stimulated growth of vascular smooth muscle cells: importance of protein kinase C-dependent synergy between estrogen and platelet-derived growth factor. J. Cell. Physiol. 166, 22-32
14. Guenther, A. E., Conley, A. J., Van Orden, D. E., Farley, D. B., and Ford, S. P. (1988) Structural and mechanical changes of uterine arteries during pregnancy in the pig. J. Anim. Sci. 66, 3144-3152
15. Fuller, R., Colton, I., Gokina, N., Mandala, M., and Osol, G. (2011) Local versus systemic influences on uterine vascular reactivity during pregnancy in the single-horn gravid rat. Reprod. Sci. 18, 723-729
16. Conrad, K. P. (2011) Maternal vasodilation in pregnancy: the emerging role of relaxin. Am. J. Physiol. 301, R267-275
17. Conrad, K. P. (2011) Emerging role of relaxin in the maternal adaptations to normal pregnancy: implications for preeclampsia. Semin. Nephrol. 31, 15-32
18. Jeyabalan, A., and Conrad, K. P. (2007) Renal function during normal pregnancy and preeclampsia. Front. Biosci. 12, 2425-2437
19. Danielson, L. A., Sherwood, O. D., and Conrad, K. P. (1999) Relaxin is a potent renal vasodilator in conscious rats. J. Clin. Invest. 103, 525-533
20. Conrad, K. P., Debrah, D. O., Novak, J., Danielson, L. A., and Shroff, S. G. (2004) Relaxin modifies systemic arterial resistance and compliance in conscious, nonpregnant rats. Endocrinology 145, 3289-3296
21. Novak, J., Ramirez, R. J. J., Gandley, R. E., Sherwood, O. D., and Conrad, K. P. (2002) Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats. Am. J. Physiol. 283, R349-R355
22. Debrah, D. O., Novak, J., Matthews, J. E., Ramirez, R. J., Shroff, S. G., and Conrad, K. P. (2006) Relaxin is essential for systemic vasodilation and increased global arterial compliance during early pregnancy in conscious rats. Endocrinology 147, 5126-5131
23. Novak, J., Danielson, L. A., Kerchner, L. J., Sherwood, O. D., Ramirez, R. J., Moalli, P. A., and Conrad, K. P. (2001) Relaxin is essential for renal vasodilation during pregnancy in conscious rats. J. Clin. Invest. 107, 1469-1475
24. Novak, J., Parry, L. J., Matthews, J. E., Kerchner, L. J., Indovina, K., Hanley-Yanez, K., Doty, K. D., Debrah, D. O., Shroff, S. G., and Conrad, K. P. (2006) Evidence for local relaxin ligandreceptor expression and function in arteries. FASEB J. 20, 2352-2362
25. Ferreira, V. M., Gomes, T. S., Reis, L. A., Ferreira, A. T., Razvickas, C. V., Schor, N., and Boim, M. A. (2009) Receptorinduced dilatation in the systemic and intrarenal adaptation to pregnancy in rats. PLoS One 4, e4845
26. Debrah, D. O., Debrah, J. E., Haney, J. L., McGuane, J. T., Sacks, M. S., Conrad, K. P., and Shroff, S. G. (2011) Relaxin regulates vascular wall remodeling and passive mechanical properties in mice. J. Appl. Physiol. 111, 260-271
27. Chan, S. L., and Cipolla, M. J. (2011) Relaxin causes selective outward remodeling of brain parenchymal arterioles via activation of peroxisome proliferator-activated receptor-gamma. FASEB J. 25, 3229-3239
28. Xu, Q., Chakravorty, A., Bathgate, R. A., Dart, A. M., and Du, X. J. (2010) Relaxin therapy reverses large artery remodeling and improves arterial compliance in senescent spontaneously hypertensive rats. Hypertension 55, 1260-1266
29. Vodstrcil, L. A., Shynlova, O., Verlander, J. W., Wlodek, M. E., and Parry, L. J. (2010) Decreased expression of the rat myometrial relaxin receptor (RXFP1) in late pregnancy is partially mediated by the presence of the conceptus. Biol. Reprod. 83, 818-824
30. Vodstrcil, L. A., Wlodek, M. E., and Parry, L. J. (2007) Effects of uteroplacental restriction on the relaxin-family receptors, Lgr7 and Lgr8, in the uterus of late pregnant rats. Reprod. Fertil. Dev. 19, 530-538
31. Vodstrcil, L. A., Shynlova, O., Westcott, K. T., Laker, R., Simpson, E., Wlodek, M. E., and Parry, L. J. (2010) Progesterone withdrawal, and not increased circulating relaxin, mediates the decrease in myometrial relaxin receptor (RXFP1) expression in late gestation in rats. Biol. Reprod. 83, 825-832
32. Wigg, S. J., Tare, M., Forbes, J., Cooper, M. E., Thomas, M. C., Coleman, H. A., Parkington, H. C., and O'Brien, R. C. (2004) Early vitamin E supplementation attenuates diabetes-associated vascular dysfunction and the rise in protein kinase C-beta in mesenteric artery and ameliorates wall stiffness in femoral artery of Wistar rats. Diabetologia 47, 1038-1046
33. Mazzuca, M. Q., Wlodek, M. E., Dragomir, N. M., Parkington, H. C., and Tare, M. (2010) Uteroplacental insufficiency programs regional vascular dysfunction and alters arterial stiffness in female offspring. J. Physiol. 588, 1997-2010
34. Sherwood, O. D., Crnekovic, V. E., Gordon, W. L., and Rutherford, J. E. (1980) Radioimmunoassay of relaxin throughout pregnancy and during parturition in the rat. Endocrinology 107, 691-698
35. Scott, D. J., Layfield, S., Yan, Y., Sudo, S., Hsueh, A. J., Tregear, G. W., and Bathgate, R. A. (2006) Characterization of novel splice variants of LGR7 and LGR8 reveals that receptor signaling is mediated by their unique low density lipoprotein class A modules. J. Biol. Chem. 281, 34942-34954
36. Crish, J. F., Soloff, M. S., and Shaw, A. R. (1986) Changes in relaxin precursor mRNA levels in the rat ovary during pregnancy. J. Biol. Chem. 261, 1909-1913
37. Gunnersen, J. M., Crawford, R. J., and Tregear, G. W. (1995) Expression of the relaxin gene in rat tissues. Mol. Cell. Endocrinol. 110, 55-64
38. Siebel, A. L., Gehring, H. M., Reytomas, I. G. T., and Parry, L. J. (2003) Inhibition of oxytocin receptor and estrogen receptor-α, but not relaxin receptors (LGR7), in the myometrium of late pregnant relaxin gene knockout mice. Endocrinology 144, 4272-4275
39. Longo, M., Jain, V., Vedernikov, Y. P., Garfield, R. E., and Saade, G. R. (2003) Effects of recombinant human relaxin on pregnant rat uterine artery and myometrium in vitro. Am. J. Obstet. Gynecol. 188, 1468-1476
40. Bani, D., Failli, P., Bello, M. G., Thiemermann, C., Bani Sacchi, T., Bigazzi, M., and Masini, E. (1998) Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. Hypertension 31, 1240-1247
41. Novak, J. (2002) Relaxin increases uterine blood flow in concious nonpregnant rats and decreases myogenic reactivity in isolated uterine arteries. FASEB J. 16, A824
42. McGuane, J. T., Debrah, J. E., Sautina, L., Jarajapu, Y. P., Novak, J., Rubin, J. P., Grant, M. B., Segal, M., and Conrad, K. P. (2011) Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinology 152, 2786-2796
43. Guico-Lamm, M. L., Voss, E. W. J., and Sherwood, O. D. (1988) Monoclonal antibodies specific for rat relaxin. I. Production and characterization of monoclonal antibodies that neutralize rat relaxin's bioactivity in vivo. Endocrinology 123, 2472-2478
44. Conrad, K. P., and Shroff, S. G. (2011) Effects of relaxin on arterial dilation, remodeling, and mechanical properties. Curr. Hypertens. Rep. 13, 409-420
45. Jacob, M. P. (2003) Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions. Biomed. Pharmacother. 57, 195-202
46. Kelly, B. A., Bond, B. C., and Poston, L. (2003) Gestational profile of matrix metalloproteinases in rat uterine artery. Mol. Hum. Reprod. 9, 351-358
47. Jeyabalan, A., Kerchner, L. J., Fisher, M. C., McGuane, J. T., Doty, K. D., and Conrad, K. P. (2006) Matrix metalloproteinase-2 activity, protein, mRNA, and tissue inhibitors in small arteries from pregnant and relaxin-treated nonpregnant rats. J. Appl. Physiol. 100, 1955-1963
48. Jeyabalan, A., Novak, J., Doty, K. D., Matthews, J., Fisher, M. C., Kerchner, L. J., and Conrad, K. P. (2007) Vascular matrix metalloproteinase-9 mediates the inhibition of myogenic reactivity in small arteries isolated from rats after short-term administration of relaxin. Endocrinology 148, 189-197
49. Stewart, D. R., Celniker, A. C., Taylor, C. A., Jr., Cragun, J. R., Overstreet, J. W., and Lasley, B. L. (1990) Relaxin in the peri-implantation period. J. Clin. Endocrinol. Metab. 70, 1771-1773
50. Anumba, D. O., El Gelany, S., Elliott, S. L., and Li, T. C. (2009) Serum relaxin levels are reduced in pregnant women with a history of recurrent miscarriage, and correlate with maternal uterine artery Doppler indices in first trimester. Eur. J. Obstet. Gyn. Reprod. Biol. 147, 41-45