Relaxin: A pregnancy hormone as central player of body fluid and circulation homeostasis

Cellular and Molecular Life Sciences

Volumn 60, Issue 4, 2003, Pages 688-700

  Dschietzig, T ^a   Stangl, K ^a  

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

Author keywords

cAMP; G protein receptor; MAP kinase; Myocardium; Nitric oxide; Peptide; Tyrosine kinase

Indexed keywords

CYCLIC AMP; G PROTEIN COUPLED RECEPTOR; HORMONE; HYPOPHYSIS HORMONE; MITOGEN ACTIVATED PROTEIN KINASE; NITRIC OXIDE; PEPTIDE; PROTEIN TYROSINE KINASE; RECEPTOR; RELAXIN;

ANGIOGENESIS; BODY FLUID; CELL DIVISION; CIRCULATION; CONNECTIVE TISSUE; HEART MUSCLE; HOMEOSTASIS; HORMONE RELEASE; IMPLANTATION; LABOR; PLEIOTROPY; PREGNANCY; REVIEW; SIGNAL TRANSDUCTION; UTERUS CONTRACTION; VASODILATATION;

BLOOD CIRCULATION; BODY FLUIDS; BRAIN; CONNECTIVE TISSUE; FEMALE; GENE EXPRESSION; GENITALIA, FEMALE; HEART; HOMEOSTASIS; HUMANS; KIDNEY; ORGAN SPECIFICITY; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, PEPTIDE; RELAXIN; SIGNAL TRANSDUCTION;

EID: 0038364161     PISSN: 1420682X     EISSN: None     Source Type: Journal    
DOI: 10.1007/s00018-003-2169-x     Document Type: Review

References (180)

1. Hisaw F. L. (1926) Experimental relaxation of the pubic ligament of guinea pig. Proc. Soc. Exp. Biol. Med. 23: 661-663
2. Fevold H. L., Hisaw F. L. and Meyer R. K. (1930) The relaxative hormone of the corpus luteum. Its purification and concentration. J. Am. Chem. Soc. 52: 3340-3348
3. Hamolsky M. and Sparrow R. C. (1945) Influence of relaxin on mammary development in sexually immature female rats. Proc. Soc. Exp. Biol. Med. 60: 8-9
4. Krantz J. C., Bryant H. H. and Carr C. J. (1950) The action of aqueous corpus luteum extract upon uterine activity. Surg. Gynecol. Obstet. 90: 372-375
5. Graham E. F. and Dracy A. E. (1953) The effect of relaxin and mechanical dilatation of the bovine cervix. J. Dairy Sci. 36: 772-777
6. Steinetz B., Beach V. L., Kroc R. L., Stasilli N. R., Nussbaum R. E., Nemith P. J. et al. (1960) Bioassay of relaxin using a reference standard: a simple and reliable method utilizing direct measurement of interpubic ligament formation in mice. Endocrinology 67: 102-115
7. Bani G. and Bigazzi M. (1984) Morphological changes induced in mouse mammary gland by porcine and human relaxin. Acta Anat. 119: 149-154
8. St. Louis J. and Massicotte G. (1985) Chronic decrease of blood pressure by rat relaxin in spontaneously hypertensive rats. Life Sci. 37: 1351-1357
9. 32P-labelled human relaxin: displaceable binding to rat uterus, cervix and brain. J. Biol. Chem. 265: 9396-9401
10. Dayanithi G., Cazalis M. and Nordmarm J. J. (1987) Relaxin affects the release of oxytocin and vasopressin from the neurohypophysis. Nature 325: 813-816
11. Hsu S. Y., Nakabayashi K, Nishi S., Kumagai J., Kudo M., Sherwood O. D. et al. (2002) Activation of orphan receptors by the hormone relaxin. Science 295: 671-674
12. Buellesbach E. E. and Schwabe C. (2001) The relaxin receptor-binding site geometry suggests a novel gripping mode of interaction. J. Biol. Chem. 275: 35276-35280
13. Palejwala S., Stein D. S., Weiss G., Monia B. P., Tortoriello D. and Goldsmith L. T. (2001) Relaxin positively regulates matrix metalloproteinase expression in human lower uterine segment fibroblasts using a tyrosine kinase signaling pathway. Endocrinology 142: 3405-3413
14. Failli P., Nistri S., Quattrone S., Mazzetti L., Bigazzi M., Bani Sacchi T. et al. (2001) Relaxin upregulates inducible nitric oxide expression and nitric oxide generation in rat coronary endothelial cells. FASEB J. 16: 252-254
15. Bathgate R. A. D., Samuel C. S., Burazin T. C. D., Layfield S., Claasz A. A., Reytomas I. G. T et al. (2001) Human relaxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene: novel members of the relaxin peptide family. J. Biol. Chem. 277: 1148-1157
16. Adham I. M., Burkhardt E., Benahmed M. and Engel W. (1993) Cloning of a cDNA for a novel insulin-like peptide of the testicular Leydig cells. J. Biol. Chem. 268: 26668-26672
17. Koman A., Cazaubon S., Vourand P. O., Ullrich A. and Strosberg A. D. (1996) Molecular characterization and in vitro biological activity of placentin, new member of the insulin gene family. J. Biol. Chem. 271: 20238-20241
18. Hsu S. Y. (1999) Cloning of two novel mammalian paralogs of relaxin/insulin family proteins and their expression in testis and kidney. Mol. Endocrinol. 13: 2163-2174
19. Schwabe C., Steinetz B. G., Weiss G., Segaloff A., McDopnald K., O'Byrne E., Hochman J. et al. (1978) Relaxin. Rec. Prog. Horm. Res. 34: 123-199
20. James R., Niall H., Kwok S. and Bryant-Greenwood G. D. (1977) Primary structure of porcine relaxin: homology with insulin and related growth factors. Nature 267: 544-546
21. Schwabe C. and McDonald J. K. (1977) Primary structure of the B-chain of porcine relaxin. Biochem. Biophys. Res. Commun. 75: 503-510
22. Schwabe C. and Buellesbach E. E. (1994) Relaxin: structures, functions, promises and nonevolution. FASEB J. 8: 1152-1160
23. Evans B. A., Fu P. and Tregear G. W. (1994) Characterization of primate relaxin genes. Endocr. J. 2: 81-86
24. Hudson P, Haley J., John M., Cronk M., Crawford R., Haralambidis J. et al. (1983) Structure of a genomic clone encoding biologically active human relaxin. Nature 301: 628-631
25. Hudson P., John M., Crawford R., Haralambidis J., Scanlon D., Gorman J. et al. (1984) Relaxin gene expression in human ovaries and the predicted structure of a human prorelaxin by analysis ofcDNA clones. EMBO J. 3: 2333-2339
26. Bryant-Greenwood G. D. and Schwabe C. (1994) Human relaxins: chemistry and biology. Endocrine Rev. 15: 5-26
27. Gunnersen J. M., Fu P., Roche P. J. and Tregear G. W. (1996) Expression of human relaxin genes: characterization of a novel alternatively-spliced human relaxin mRNA species. Mol. Cell. Endocrinol. 118: 85-94
28. Smeekens S. P., Montag A. G., Thomas G., Albiges-Rizo C, Carroll R., Benig M. et al. (1992) Proinsulin processing by the subtilisin-related proprotein convertases furin, PC 2, and PC 3. Proc. Natl. Acad. Sci. USA 89: 8822-8826
29. Marriott D., Gillece-Castro B. and Gorman C. M. (1992) Prohormone convertase-1 will process prorelaxin, a member of the insulin family of hormones. Mol. Endocrinol. 6: 1441-1450
30. Ivell R., Hund N., Khan-Dawood F. and Dawood M.Y. (1989) Expression of the human relaxin gene in the corpus luteum of the menstrual cycle and in the prostate. Mol. Cell. Endocrinol. 66: 251-255
31. Hansell D. J., Bryant-Greenwood G. D. and Greenwood F. C. (1991) Expression of the human relaxin H1 in the decidua, trophoblast, and prostate. J. Clin. Endocrinol. Metab. 72: 899-904
32. Tashima L. S., Mazoujian G. and Bryant-Greenwood G. D. (1994) Human relaxins in normal, benign and neoplastic breast tissue. J. Mol. Endocrinol. 12: 351-364
33. Dschietzig T., Richter C., Bartsch C., Laule M., Armbruster F. P., Baumann G. et al. (2001) The pregnancy hormone relaxin is a player in human heart failure. FASEB J. 15: 2187-2195
34. Bigazzi M., Nardi E., Bruni P. and Petrucci F. (1980) Relaxin in human decidua. J. Clin. Endocrinol. Metab. 51: 939-941
35. Sakbun V., Ali S. M., Greenwood F. C. and Bryant-Greenwood G. D. (1990) Human relaxin in the amnion, chorion, decidua parietalis, basal plate, and placental trophoblast by immunocytochemistry and northern analysis. J. Clin. Endocrinol. Metab. 70: 508-514
36. Fields P. A., Lee A. B., Haab L. M., Hwang J. and Sherwood D. (1992) Evidence for a dual source of relaxin in the pregnant rat: immunolocalization in the corpora lutea and endometrium. Endocrinology 130: 2985-2990
37. Essig M., Schoenfeld C., D'Eletto R., Amelar R., Oubin L. and Steinetz B. G. (1982) Relaxin in human seminal plasma. Ann. N. Y. Acad. Sci. 380: 224-230
38. Winslow J. W., Shih A., Bourell J. H., Weiss G., Reed B., Stults J. T. et al. (1990) Human seminal relaxin is a product of the same gene as human luteal relaxin. Endocrinology 130: 2660-2668
39. Taylor M. J. and Clark C. L. (1994) Evidence for a novel source of relaxin: atrial cardiocytes. J. Endocrinol. 143: R5-R8
40. Osheroff P. L. and Ho W. H. (1993) Expression of relaxin mRNA and relaxin receptors in postnatal and adult rat brains and hearts. Localization and developmental patterns. J. Biol. Chem. 268: 15193-15199
41. 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
42. Goldsmith L. T., Crob H. S., Scherer K. J., Surve A., Steinetz B. G. and Weiss G. (1981) Placental control of ovarian immunoreactive relaxin secretion in the pregnant rat. Endocrinology 109: 548-552
43. Lao Guico M. S. and Sherwood O. D. (1985) Effect of estradiol-17 beta on ovarian and serum concentrations of relaxin during the second half of pregnancy in the rat. J. Reprod. Fertil. 74: 65-70
44. Sherwood O. D., Golos T. G. and Key R. H. (1986) Influence of the conceptuses and the material pituitary on the distribution of multiple components of serum relaxin immunoreactivity during pregnancy in the rat. Endocrinology 119: 2143-2147
45. Peters C. A., Maizels E. T., Robertson M. C., Shiu R. P. C., Soloff M. S. and Hunzicker-Dunn M. (2000) Induction of relaxin messenger RNA expression inresponse to prolactin receptor activation requires protein kinase C δ signaling. Mol. Endocrinol. 14: 576-590
46. Loeken M. R., Channing C. P., D'Eletto R. and Weiss G. (1983) Stimulatory effect of luteinizing hormone upon relaxin secretion by cultured porcine preovulatory granulosa cells. Endocrinology 112: 769-771
47. Quagliarello J., Goldsmith L., Steinetz B., Lustig D. S. and Weiss G. (1980) Induction of relaxin secretion in nonpregnant women by human chorionic gonadotropin. J. Clin. Endocrinol. Metab. 51: 74-77
48. Gagliardi C. L., Goldsmith L. T., Saketos M., Weiss G. and Schmidt C. L. (1992) Human chorionic gonadotropin stimulation of relaxin secretion by luteinized human granulosa cells. Fertil. Steril. 58: 314-320
49. Bagnell C. A., Tsark W., Tashima L., Downey B. R., Tsang B K. and Ainsworth L. (1990) Relaxin gene expression in the porcine follicle during preovulatory development induced by gonadotrophins. J. Mol. Endocrinol. 5: 211-219
50. Ottobre A. C., Ramsey K. R. and Ottobre J. S. (1991) Acute versus chronic effects of human chorionic gonadotrophin on relaxin secretion in rhesus monkeys. J. Reprod. Fertil. 91: 313-320
51. Taylor M. J. and Clark C. L. (1992) Basic fibroblast growth factor inhibits basal and stimulated relaxin secretion by cultured porcine luteal cells: analysis by reverse hemolytic plaque assay. Endocrinology 130: 1951-1956
52. Bryant-Greenwood G. D. (1972) The detection of relaxin in porcine, ovine and human plasma by radioimmunoassay. Endocrinology 91: 1113-1117
53. 125I-labelled polytyrosyl-relaxin. Endocrinology 96: 1106-1113
54. Sherwood O. D. and Crnekovic V. E. (1979) Development of a homologous radioimmunoassay for rat relaxin. Endocrinology 104: 893-897
55. Bani D. (1997) Relaxin: a pleiotropic hormone. Gen. Pharmacol. 28: 13-22
56. Bell R. J., Eddie L. W., Lester A. R., Wood E. C., Johnston P. D. and Niall H. D. (1987) Relaxin in human pregnancy serum measured with an homologous radioimmunoassay. Obstet. Gynecol. 69: 585-589
57. Stewart D. R., Celniker A. C., Taylor C. A., Cragun J. R., Overstreet J. W. and Lasley B. L. (1990) Relaxin in the peri-implantation period. J. Clin. Endocrinol. Metab. 70: 1771-1773
58. rd International Conference on Relaxin and Related Peptides (Broome, Australia), pp. 273-274, Tregear G. W., Ivell R., Bathgate R. A. and Wade J. D. (eds), Kluwer, Dordrecht, The Netherlands
59. 125I-labeled porcine relaxin. J. Reprod. Fertil. 53: 209-212
60. 125I-relaxin to rat uterus. J. Biol. Chem. 255: 3617-3621
61. 125I-labeled succinylated porcine relaxin to human and mouse fibroblasts. J. Reprod. Fertil. 58: 43-49
62. Mercado-Simmen R. C., Bryant-Greenwood G. D. and Greenwood F. C. (1982) Relaxin receptor in the rat myometrium: regulation by estrogen and relaxin. Endocrinology 110: 220-226
63. Wiqvist N. (1959) The effect of prolonged administration of relaxin on some functional properties of the non-pregnant rat and mouse uterus. Acta Endocrinol. 46: 16-19
64. Wiqvist N. (1959) Desensitizing effect of exo- and endogenous relaxin on the immediate uterine response to relaxin. Acta Endocrinol. 46: 3-8
65. Osheroff P. L. and Phillips H. S. (1991) Autoradiographic localization of relaxin binding sites in rat brain. Proc. Natl. Acad. Sci. USA 88: 6413-6417
66. Osheroff P. L., Cronin M. J. and Lofgren J. A. (1992) Relaxin binding in the rat heart atrium. Proc. Natl. Acad. Sci. USA 89: 2384-2388
67. 32p-labeled human relaxin to human uterine cells and primary rat atrial cardiomyocytes. Endocrinology 136: 4377-4381
68. Tan Y. Y., Wade J. D., Tregear G. W. and Summers R. J. (1998) Comparison of relaxin receptors in rat isolated atria and uterus by use of synthetic and native relaxin analogues. Br. J. Pharmacol. 123: 762-770
69. Tan Y. Y., Wade J. D., Treagear G. W. and Summers R. J. (1999) Quantitative autoradiographic studies of relaxin binding in rat atria, uterus and cerebral cortex: characterization and effects of oestrogen treatment. Br. J. Pharmacol. 127: 91-98
70. Buellesbach E. E. and Schwabe C. (1988) On the receptor binding site of relaxins. Int. J. Peptide Protein Res. 32: 361-367
71. Buellesbach E. E., Yang S. and Schwabe C. (1991) Total synthesis of human relaxin and human relaxin derivatives by solid-phase peptide synthesis and site-directed chain combination. J. Biol. Chem. 266: 10754-10761
72. Buellesbach E. E. and Schwabe C. (1992) The receptor-binding site of human relaxin II. A dual prong-binding mechanism. J. Biol. Chem. 267: 22957-22960
73. Einspanier A., Mueller D., Lubberstedt J., Bartsch O., Jurdzinski A., Fuhrmann K. et al. (2001) Characterization of relaxin binding in the uterus of the marmorset monkey. Mol. Hum. Reprod. 7: 963-970
74. Mathieu M. N., Wade J. D., Tregear G. W., Bond C. P., Summers R. J., Catimel B. et al. (2001) Synthesis, conformational studies and biological activity of biotinylated rat relaxin. J. Peptide Res. 57: 374-382
75. Ivell R. (2002) This hormone has been relaxin' too long! Science 295: 637-638
76. Braddon S. A. (1978) Relaxin-dependent adenosine 3′, 5′-monophosphate concentration changes in the mouse pubic symphysis. Endocrinology 102: 1292-1299
77. Sanborn B. M., Kuo H. S., Weisbrodt N. W. and Sherwood O. D. (1980) The interaction of relaxin with the rat uterus. I. Effect on cyclic nucleotide levels and spontaneous contractile activity. Endocrinology 106: 1210-1215
78. Hsu C. J., McCormack S. M. and Sanborn B. M. (1985) The effect of relaxin on cyclic adenosine 3′, 5′-monophosphate concentration in rat myometrial cells in culture. Endocrinology 116: 2029-2035
79. Chen G., Huang J. R. and Tseng L. (1988) The effect of relaxin on cyclic adenosine 3′, 5′-monophosphate concentrations in human endometrial glandular epithelial cells. Biol. Reprod. 39: 519-525
80. Fei D. T. W., Gross M. C., Lofgren J. L., Mora-Worms M. and Chen A. B. (1990) Cyclic AMP response to recombinant human relaxin by cultured human endometrial cells - a specific and high throughput in vitro bioassay. Biochem. Biophys. Res. Commun. 170: 214-222
81. Bigazzi M., Brandi M. L., Bani G. and Bani Sacchi T. (1992) Relaxin influences the growth of MCF-7 breast cancer cells. Mitogenic and antimitogenic action depends on peptide concentration. Cancer 70: 639-643
82. Cronin M. J., Malaska T. and Bakhit C. (1987) Human relaxin increases cyclic AMP levels in cultured anterior pituitary cells. Biochem. Biophys. Res. Commun. 148: 1246-1251
83. Toth M, Taskinen P. and Ruskoaho H. (1996) Relaxin stimulates atrial natriuretic peptide secrretion in perfused rat heart. J. Endocrinol. 150: 487-495
84. Piedras-Renteria E. S., Sherwood O. D. and Best P. M. (1997) Effects of relaxin on rat atrial myocytes. I. Inhibition of I(to) via PKA-dependent phosphorylation. Am. J. Physiol. 272: H1791-H1797
85. Bartsch O., Bartlick B. and Ivell R. (2001) Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity. Mol. Hum. Reprod. 7: 799-809
86. Masini E., Bani D., Bigazzi M., Mannaioni P. F. and Bani-Sacchi T. (1994) Effects of relaxin on mast cells. In vitro and in vivo studies in rats and guinea pigs. J. Clin. Invest. 94: 1974-1980
87. Bani-Sacchi T., Bigazzi M., Bani D., Mannaioni P. F. and Masini E. (1995) Relaxin-induced increased coronary flow through stimulation of nitric oxide production. Br. J. Pharmacol. 116: 1589-1594
88. Bani D., Bigazzi M., Masini E., Bani G. and Sacchi T. B. (1995) Relaxin depresses platelet aggregation: in vitro studies on isolated human and rabbit platelets. Lab. Invest. 73: 709-716
89. Bani D., Masini E., Bello M. G., Bigazzi M. and Sacchi T. B. (1995) Relaxin activates the L-arginine-nitric oxide pathway in human breast cancer cells. Cancer Res. 55: 5272-5275
90. Bani D., Baccari M. C., Quattrone S., Nistri S., Calamai F., Bigazzi M. et al. (2002) Relaxin depresses small bowel motility through a nitric oxide-mediated mechanism. Studies in mice. Biol. Reprod. 66: 778-784
91. Bani D., Failli P., Bello M. G., Thiemermann C., Bani Sacchi T, Bigazzi M. et al. (1998) Relaxin activates the L-arginine-nitric oxide pathway in vascular smooth muscle cells in culture. Hypertension 31: 1240-1247
92. Bani D., Baccari M. C., Nistri S., Calamai F., Bigazzi M. and Sacchi T. B. (1999) Relaxin up-regulates the nitric oxide biosynthetic pathway in the mouse uterus: involvement in the inhibition of myometrial contractility. Endocrinology 140: 4434-4441
93. Zhang Q., Liu S. H., Erikson M., Lewis M. and Unemori E. (2002) Relaxin activates the MAP kinase pathway in human endometrial stromal cells. J. Cell. Biochem 85: 536-544
94. Zarreh-Hoshyari-Khah R., Bartsch O., Einspanier A., Pohnke Y. and Ivell R. (2001) Bioactivity of recombinant prorelaxin from the marmoset monkey. Regul. Pept. 97: 139-146
95. Sherwood O. D. (1994) Relaxin. In: The Physiology of Reproduction, 2nd edition, Knobil E. and Neill J. (eds), 861-1010. New York, Raven Press
96. Goldsmith L. T., Weiss G. and Steinetz B. G. (1995) Relaxin and its role in pregnancy. Endocrinol. Metab. Clin. North Am. 24: 171-186
97. Kelly A. J., Kavanagh J. and Thomas J. (2001) Relaxin for cervical ripening and induction of labour. Cochrane Database Syst. Rev. 2: CD003103
98. Weiss G. and Goldsmith L. T. (2001) Relaxin and the cervix. Front. Horm. Res. 27: 105-112
99. Telgmann R. and Gellersen B. (1998) Marker genes of decidualization: activation of the decidual prolactin gene. Hum. Reprod. Update 4: 472-479
100. Tseng L. and Mazella J. (1999) Prolactin and its receptor in human endometrium. Semin. Reprod. Endocrinol. 17: 23-27
101. Bani G., Maurizi M., Bigazzi M. and Bani Sacchi T. (1995) Effects of relaxin on the endometrial stroma. Studies in mice. Biol. Reprod. 53: 253-262
102. Sunder S. and Lenton E. A. (2000) Endocrinology of the periimplantation period. Baillieres Best Pract. Res. Clin. Obstet. Gynaecol. 14: 789-800
103. Seppala M., Koistinen H. and Koistinen R. (2001) Glycodelins. Trends Endocrinol. Metab. 12: 111-117
104. Meera P., Anwer K., Monga M., Oberti C., Stefani E., Toro L. et al. (1995) Relaxin stimulates myometrial calcium-activated potassium channel activity via protein kinase A. Am. J. Physiol. 269: C312-C317
105. Hughes S. J. and Hollingsworth M. (1996) The lack of a role for potassium channel opening in the action of relaxin in the rat isolated uterus; a comparison with levcromakalim and salbutamol. Br. J. Pharmacol. 117: 1435-1442
106. MacLennan A. H., Grant P., Ness D. and Down A. (1986) Effect of porcine relaxin and progesterone on rat, pig and human myometrial activity in vitro. J. Reprod. Med. 31: 43-49
107. MacLennan A. H. and Grant P. (1991) Human relaxin. In vitro response of human and pig myometrium. J. Reprod. Med. 36: 630-634
108. Petersen L. K., Svane D., Uldbjerg N. and Forman A. (1991) Effects of human relaxin on isolated rat and human myometrium and uteroplacental arteries. Obstet. Gynecol. 78: 757-762
109. MacLennan A. H., Grant P. and Bryant-Greenwood G. (1995) hRLX-1. In vitro response of human and pig myometrium. J. Reprod. Med. 40: 703-706
110. Bani G., Bigazzi M. and Bani D. (1985) Effects of relaxin on the mouse mammary gland. I. The myoepithelial cells. J. Endocrinol. Invest. 8: 207-215
111. Bani G., Bigazzi M. and Bani D. (1986) The effects of relaxin on the mouse mammary gland. II. The epithelium. J. Endocrinol. Invest. 9: 145-152
112. Bianchi S., Bani G. and Bigazzi M. (1986) Effects of relaxin on the mouse mammary gland. III. The fat pad. J. Endocrinol. Invest. 9: 153-160
113. Hwang J. J., Lee A. B., Fields P. A., Haab L. M., Mojonnier L. E. and Sherwood O. D. (1991) Monoclonal antibodies specific for rat relaxin. V. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts development of the mammary apparatus and, hence, lactational performance in rats. Endocrinology 129: 3034-3042
114. Kuenzi M. J. and Sherwood O. D. (1992) Monoclonal antibodies specific for rat relaxin. VII. Passive immunization with monoclonal antibodies throughout the second half of pregnancy prevents development of normal mammary nipple morphology and function in rats. Endocrinology 131: 1841-1847
115. Kuenzi M. J., Connolly B. A. and Sherwood O. D. (1995) Relaxin acts directly on rat mammary nipples to stimulate their growth. Endocrinology 136: 2943-2947
116. Mazoujian G. and Bryant-Greenwood G. D. (1990) Relaxin in breast tissue. Lancet 335: 298-29
117. Bigazzi M., Brandi M. L., Bani G. and Sacchi T. B. (1992) Relaxin influences the growth of MCF-7 breast cancer cells. Mitogenic and antimitogenic action depends on peptide concentration. Cancer 70: 639-643
118. Bani D. (1997) Relaxin and breast cancer. Bull. Cancer 84: 179-182
119. Too C. K., Bryant-Greenwood G. D. and Greenwood F. C. (1984) Relaxin increases the release of plasminogen activator, collagenase, and proteoglycanase from rat granulosa cells in vitro. Endocrinology 115: 1043-1050
120. Downing S. J. and Sherwood O. D. (1986) The physiological role of relaxin in the pregnant rat. IV. The influence of relaxin on cervical collagen and glycosaminoglycans. Endocrinology 118: 471-479
121. Samuel C. S., Butkus A., Coghlan J. P. and Bateman J. F. (1996) The effect of relaxin on collagen metabolism in the nonpregnant rat pubic symphysis: the influence of estrogen and progesterone in regulating relaxin activity. Endocrinology 137: 3884-3890
122. Unemori E. N. and Amento E. P. (1990) Relaxin modulates synthesis and secretion of procollagenase and collagen by human dermal fibroblasts. J. Biol. Chem. 265: 10681-10685
123. Unemori E. N., Pickford L. B., Salles A. L., Piercy C. E., Grove B. H., Erikson M. E. et al. (1996) Relaxin induces an extracellular matrix-degrading phenotype in human lung fibroblasts in vitro and inhibits lung fibrosis in a murine model in vivo. J. Clin. Invest. 98: 2739-2745
124. Unemori E. N., Beck L. S., Lee W. P., Xu Y., Siegel M., Keller G. et al. (1993) Human relaxin decreases collagen accumulation in vivo in two rodent models of fibrosis. J. Invest. Dermatol. 101: 280-285
125. Garber S. L., Mirochnik Y., Brecklin C. S., Unemori E. N., Singh A. K., Slobodskoy L. et al. (2001) Relaxin decreases renal interstitial fibrosis and slows progression of renal disease. Kidney Int. 59: 876-882
126. Williams E. J., Benyon R. C., Trim N., Hadwin R., Grove B. H., Arthur M. J. et al. (2001) Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut 49: 577-583
127. Seibold J. R., Korn J. H., Simms R., Clements P. J., Moreland L. W., Mayes M. D. et al. (2002) Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 132: 871-879
128. rd International Conference on Relaxin and Related Peptides (Broome, Australia), pp. 373-381, Tregear G. W., Ivell R., Bathgate R. A. and Wade J. D. (eds), Kluwer, Dordrecht, The Netherlands
129. Summerlee A. J., O'Byrne K. T., Paisley A. C., Breeze M. F. and Porter D. G. (1984) Relaxin affects the central control of oxytocin release. Nature 309: 372-374
130. O'Byrne K. T., Eltringham L., Clarke G. and Summerlee A. J. (1986) Effects of porcine relaxin on oxytocin release from the neurohypophysis in the anaesthetized lactating rat. J. Endocrinol. 109: 393-397
131. Way S. A. and Leng G. (1992) Relaxin increases the firing rate of supraoptic neurones and increases oxytocin secretion in the rat. J. Endocrinol. 132: 149-158
132. Parry L. J. and Summerlee A. J. (1991) Central angiotensin partially mediates the pressor action of relaxin in anesthetized rats. Endocrinology 129: 47-52
133. Geddes B. J., Parry L. J. and Summerlee A. J. (1994) Brain angiotensin-II partially mediates the effects of relaxin on vasopressin and oxytocin release in anesthetized rats. Endocrinology 134: 1188-1192
134. Yang R. H., Bunting S., Wyss J. M., Berecek K. H., Zhang L. and Jin H. (1995) Pressor and bradycardic effects of centrally administered relaxin in conscious rats. Am. J. Hypertens. 8: 375-381
135. Geddes B. J. and Summerlee A. J. (1995) The emerging concept of relaxin as a centrally acting peptide hormone with hemodynamic actions. J. Neuroendocrinol. 7: 411-417
136. Summerlee A. J., Hornsby D. J. and Ramsey D. G. (1998) The dipsogenic effects of rat relaxin: the effect of photoperiod and the potential role of relaxin on drinking in pregnancy. Endocrinology 139: 2322-2328
137. Hornsby D. J., Wilson B. C. and Summerlee A. J. (2001) Relaxin and drinking in pregnant rats. Prog. Brain Res. 133: 229-240
138. Sunn N., Egli M., Burazin T. C., Burns P., Colvill L., Davern P. et al. (2002) Circulating relaxin acts on subfornical organ neurons to stimulate water drinking in the rat. Proc. Natl. Acad. Sci. USA 99: 1701-1706
139. Weisinger R. S., Burns P., Eddie L. W. and Wintour E. M. (1993) Relaxin alters the plasma osmolality-arginine vasopressin relationship in the rat. J. Endocrinol. 137: 505-510
140. 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
141. Summerlee A. J., O'Byrne K. T., Jones S. A. and Eltringham L. (1987) The subfornical organ and relaxin-induced inhibition of reflex milk ejection in lactating rats. J. Endocrinol. 115: 347-353
142. McKinley M. J., Pennington G. L. and Oldfield B. J. (1996) Anteroventral wall of the third ventricle and dorsal lamina terminalis: headquarters for control of body fluid homeostasis? Clin. Exp. Pharmacol. Physiol. 23: 271-281
143. Sunn N., McKinley M. J. and Oldfield B. J. (2001) Identification of efferent neural pathways from the lamina terminalis activated by blood-borne relaxin. J. Neuroendocrinol. 13: 432-437
144. Sortino M. A., Cronin M. J. and Wise P. M. (1989) Relaxin stimulates prolactin secretion from anterior pituitary cells. Endocrinology 124: 2013-2015
145. Bethea C. L., Cronin M. J., Haluska G. J. and Novy M. J. (1989) The effect of relaxin infusion on prolactin and growth hormone secretion in monkeys. J. Clin. Endocrinol. Metab. 69: 956-962
146. Summerlee A. J., Mumford A. D. and Smith M. S. (1991) Porcine relaxin affects the release of luteinizing hormone in rats. J. Neuroendocrinol. 3: 133-138
147. Vasilenko P., Mead J. P. and Weidmann J. E. (1986) Uterine growth-promoting effects of relaxin: a morphometric and histological analysis. Biol. Reprod. 35: 987-995
148. Bigazzi M., Del Mese A., Petrucci F., Casali R. and Novelli G. P. (1986) The local administration of relaxin induces changes in the microcirculation of the rat mesocaecum. Acta Endocrinol. 112: 296-299
149. Bani D., Nistri S., Quattrone S., Bigazzi M. and Bani Sacchi T. (2001) The vasorelaxant hormone relaxin induces changes in liver sinusoid microcirculation: a morphologic study in the rat. J. Endocrinol. 171: 541-549
150. Novak J., Ramirez R. 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
151. Danielson L. A., Kercher L. J. and Conrad K. P. (2000) Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. Am. J. Physiol. 279: R1298-R1304
152. Novak J., Danielson L. A., Kerchner L. J., Sherwood O. D., Ramirez R. J., Moalli P. A. et al. (2001) Relaxin is essential for renal vasodilation during pregnancy in conscious rats. J. Clin. Invest. 107: 1469-1475
153. Miyauchi T. and Masaki T. (1999) Pathophysiology of endothelin in the cardiovascular system. Annu. Rev. Physiol. 61: 391-415
154. Unemori E. N., Erikson M. E., Rocco S. E., Sutherland K. M., Parsell D. A., Mak J. et al. (1999) Relaxin stimulates expression of vascular endothelial growth factor in normal human endometrial cells in vitro and is associated with menometrorrhagia in women. Hum. Reprod. 14: 800-806
155. Unemori E. N., Lewis M., Constant J., Arnold G., Grove B. H., Normand J. et al. (2000) Relaxin induces vascular endothelial growth factor expression and angiogenesis selectively at wound sites. Wound Repair Regen. 8: 361-370
156. Palejwala S., Tseng L., Wojtczuk A., Weiss G. and Goldsmith L. T. (2002) Relaxin gene and protein expression and its regulation of procollagenase and vascular endothelial growth factor in human endometrial cells. Biol. Reprod. 66: 1743-1748
157. Parry L. J., Potershi R. S., Summerlee A. J. and Jones S. A. (1990) Mechanisms of the haemotensive action of porcine relaxin in anaesthetised rats. J. Neuroendocrinol. 2: 53-58
158. Kakouris H., Eddie L. W. and Summers R. J. (1992) Cardiac effects of relaxin in rats. Lancet 339: 1076-1078
159. Ward D. G.,Thomas G. R. and Cronin M. J. (1992) Relaxin increases rat heart rate by a direct action on the cardiac atrium. Biochem. Biophys. Res. Commun. 186: 999-1005
160. Thomas G. R. and Vandlen R. (1993) The purely chronotropic effects of relaxin in the rat isolated heart. J. Pharm Pharmacol. 45: 927-928
161. Han X., Habuchi Y. and Giles W. R. (1994) Relaxin increases heart rate by modulating calcium current in cardiac pacemaker cells. Circ. Res. 74: 537-541
162. Piedras-Renteria E. S., Sherwood O. D. and Best P. M. (1997) Effects of relaxin on rat atrial myocytes. II. Increased calcium influx derived from action potential prolongation. Am. J. Physiol. 272: H1798-H1803
163. Masini E., Salvemini D., Mugnai L., Bello M. G., Bani D. and Mannaioni P. F. (1996) The effect of relaxin on myocardial ischaemia-reperfusion injury and histamine release in vitro and in vivo. Inflamm. Res. 45: S27-S28
164. Masini E., Bani D., Bello M. G., Bigazzi M., Mannaioni P. F. and Sacchi T. B. (1997) Relaxin counteracts myocardial damage induced by ischemia-reperfusion in isolated guinea pig hearts: evidence for an involvement of nitric oxide. Endocrinology 138: 4713-4720
165. Bani D., Masini E., Bello M. G., Bigazzi M. and Sacchi T. B. (1998) Relaxin protects against myocardial injury caused by ischemia and reperfusion in rat heart. Am. J. Pathol. 152: 1367-1376
166. rd International Conference on Relaxin and Related Peptides (Broome, Australia), pp. 293-298, Tregear G. W., Ivell R., Bathgate R. A. and Wade J. D. (eds), Kluwer, Dordrecht, The Netherlands
167. De Bold A. J., Bruneau B. G. and Kuroski de Bold M. L. (1996) Mechanical and neuroendocrine regulation of the endocrine heart. Cardiovasc. Res. 31: 7-18
168. Stangl K., Dschietzig T., Richter C., Laule M., Stangl V., Tanis E. et al. (2000) Pulmonary release and coronary and peripheral consumption of big endothelin and endothelin-1 in severe heart failure: acute effects of vasodilator therapy. Circulation 102: 1132-1138
169. Dschietzig T, Richter C., Bartsch C., Boehme C., Heinze D., Ott F. et al. (2001) Flow-induced pressure differentially regulates endothelin-1, urotensin II, adrenomedullin and relaxin in pulmonary vascular endothelium. Biochem. Biophys. Res. Commun. 289: 245-251
170. Bani D., Bigazzi M., Masini E., Bani G. and Sacchi T. B. (1995) Relaxin depresses platelet aggregation: in vitro studies on isolated human and rabbit platelets. Lab. Invest. 73: 709-716
171. Bani D., Maurizi M. and Bigazzi M. (1995) Relaxin reduces the number of circulating platelets and depresses platelet release from megakaryocytes: studies in rats. Platelets 6: 330-335
172. Qin X., Garibay-Tupas J., Chua P. K., Cachola L. and Bryant-Greenwood G. D. (1997) An autocrine/paracrine role of human decidual relaxin. I. Interstitial collagenase (matrix metalloproteinase-1) and tissue plasminogen activator. Biol. Reprod. 56: 800-811
173. Wang-Lee J. L., Lenhart J. A., Ohleth K. M., Ryan P. L. and Bagnell C. A. (1998) Regulation of urokinase- and tissue-type plasminogen activator by relaxin in the uterus and cervix of the prepubertal gilt. J. Reprod. Fertil. 114: 119-125
174. Bani D., Ballati L., Masini E., Bigazzi M. and Sacchi T. B. (1997) Relaxin counteracts asthma-like reaction induced by inhaled antigen in sensitized guinea pigs. Endocrinology 138: 1909-1915
175. Piccinni M. P., Bani D., Beloni L., Manuelli C., Mavilia C., Vocioni F. et al. (1999) Relaxin favors the development of activated human T cells into Th1-like effectors. Eur. J. Immunol. 29: 2241-2247
176. Piccinni M. P., Maggi E. and Romagnani S. (2000) Environmental factors favoring the allergen-specific Th2 response in allergic subjects. Ann. N. Y. Acad. Sci. 917: 844-852
177. rd International Conference on Relaxin and Related Peptides (Broome, Australia), pp. 273-281, Tregear G. W., Ivell R., Bathgate R. A. and Wade J. D. (eds), Kluwer, Dordrecht, The Netherlands
178. Hulley S., Grady D., Bush T., Furberg C., Herrington D., Riggs B. et al. (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280: 605-613
179. Herrington D. M., Reboussin D. M., Brosnihan K. B., Sharp P. C., Shumaker S. A., Snyder T. E. et al. (2000) Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N. Engl. J. Med. 343: 522-529
180. Bigazzi M., Bani D. and Bani Sacchi T. (2001) Relaxin: a possible future preventive therapy for cardiovascular disease in postmenopausal women and men? Climacteric 4: 137-143