Relaxin is a protein hormone, produced and secreted during pregnancy in mammalian species, having superficial structural features resembling those of insulin. Since its initial isolation from the ovaries of pregnant pigs in 1976, increasing interest in relaxin has led to increased understanding of the chemistry, synthesis, secretion, biological roles, mechanisms of action, and potential clinical applications of relaxin in humans and domestic animals. In pigs, rats, and mice, relaxin promotes growth and softening of the cervix, enabling rapid and safe delivery of the fetuses. In these species relaxin also promotes growth and development of the mammary apparatus. Recently, biological effects of relaxin in the heart, kidney, liver, and brain have been identified, and these discoveries have triggered additional interest in possible clinical applications for relaxin. In 2002, a second form of relaxin, which is found primarily in the brain, was discovered. Relaxin-like factor (also called insulin 3), which was discovered in 1993, is produced in the fetal testis and plays a major role in testicular descent during development. The recent identification of the receptors for both relaxin and relaxin-like factor has enabled more rigorous studies of the target tissues and mechanisms of action of these hormones. This volume contains a description of recent advances and future research and clinical possibilities in the field of relaxin and related peptides. NOTE: Annals volumes are available for sale as individual books or as a journal. For information on institutional journal subscriptions, please visit www.blackwellpublishing.com/nyas. ACADEMY MEMBERS: Please contact the New York Academy of Sciences directly to place your order (www.nyas.org). Members of the New York Academy of Science receive full-text access to the Annals online and discounts on print volumes. Please visit http://www.nyas.org/MemberCenter/Join.aspx for more information about becoming a member.

Table of Contents:
Preface (O David Sherwood). Young Investigator Award Recipients. Remembrance: Edmund S. Crelin (1923-2004) (Bernard G. Steinetz). Opening Remarks: An "Old Hand's" Perspective of Relaxin 2004's Place Along the Relaxin Trail (O David Sherwood). In Memoriam: Robert L. Kroc—A Relaxin Pioneer and So Much More (Bernard G. Steinetz). Part I: Structure/Activity Aspects of Relaxin, Relaxin-Related Peptides, and Their Receptors. 1. Relaxin Research in the Postgenomic Era (Kazuhiro Kawamura, Satoko Sudo, Jin Kumagai, Margareta Pisarska, Sheau Yu Teddy Hsu, Ross Bathgate, John Wade, And Aaron J. W. Hsueh). 2. Characterization of the Mouse and Rat Relaxin Receptors (D J Scott, S Layfield, A Riesewijk, H Morita, G W Tregear, And R A D Bathgate). 3. Characterization of the Rat INSL3 Receptor (D J Scott, P Fu, P-J Shen, A Gundlach, S Layfield, A Riesewijk, H Tomiyama, J M Hutson, G W Tregear, And R A D Bathgate). 4. Identification of Binding Sites with Differing Affinity and Potency for Relaxin Analogues on LGR7 and LGR8 Receptors (Michelle L. Halls, Ross A. Bathgate, Satoko Sudo, Jin Kumagai, Courtney P. Bond, And Roger J. Summers). 5. LGR7-Truncate Is a Splice Variant of the Relaxin Receptor LGR7 and Is a Relaxin Antagonist in Vitro (D J Scott, G W Tregear, And R A D Bathgate). 6. The Human LGR7 Low-Density Lipoprotein Class A Module Requires Calcium for Structure (Emma J. Hopkins, Ross A. Bathgate, And Paul R. Gooley). 7. Studies on Soluble Ectodomain Proteins of Relaxin (LGR7) and Insulin 3 (LGR8) Receptors (Yan Yan, Jin Cai, Ping Fu, Sharon Layfield, Tania Ferraro, Jin Kumagai, Satoko Sudo, Jian-Guo Tang, Eleni Giannakis, Geoffrey W. Tregear, John D. Wade, And Ross A.D. Bathgate). 8. The Chemistry and Biology of Human Relaxin-3 (Geoffrey W. Tregear, Ross A. Bathgate, Sharon Layfield, Tania Ferraro, Andrew Gundlach, Sherie Ma, Feng Lin, Nicola F. Hanson, Roger J. Summers, Johan Rosengren, David J. Craik, And John D. Wade). 9. Recent Progress in Relaxin-3-Related Research (Changlu Liu, Pascal Bonaventure, Steven W. Sutton, Jingcai Chen, Chester Kuei, Diane Nepomuceno, and Timothy W. Lovenberg). 10. Receptors for Relaxin Family Peptides (Ross A. Bathgate, Richard Ivell, Barbara M. Sanborn, O David Sherwood, And Roger J. Summers). 11. Expression of Porcine Prorelaxin in Transgenic Tobacco (Scott Buswell, Fabricio Medina-Bolivar, Qiang Chen, Kevin Van Cott, And Chenming Zhang). Part IIA: Actions of Relaxin: Reproductive Tissues during Pregnancy. 12. Genetic Targeting of Relaxin and Insl3 Signaling in Mice (Shu Feng, Natalia V. Bogatcheva, Aparna A. Kamat, And Alexander I. Agoulnik). 13. Mechanisms of Relaxin Action in the Reproductive Tract: Studies in the Relaxin-Deficient (Rlx–/–) Mouse (Laura J. Parry, Jonathan T. McGuane, Helen M. Gehring, Irna Grace T. Kostic, and Andrew L. Siebel). 14. Oxytocin and Estrogen Receptor Expression in the Myometrium of Pregnant Relaxin-Deficient (Rlx–/–) Mice (Andrew L. Siebel, Helen M. Gehring, Lenka Vodstrcil, And Laura J. Parry). 15. Relaxin Regulates Endometrial Structure and Function in the Rhesus Monkey (Laura T. Goldsmith And Gerson Weiss). 16. Effects of the Sucking Stimulus on Relaxin Receptor (LGR7) Expression in the Mammary Apparatus of the Tammar Wallaby (Macropus eugenii) (Janey Gwyther, Helen M. Gehring, and Laura J. Parry). 17. Potential Binding Sites for Relaxin in Pregnant Rabbits (Phillip A. Fields and Michael J. Fields). Part IIB: Actions of Relaxin: Reproductive Tissues in Nonpregnant Animals. 18. Porcine and Human Relaxin Bioactivity: Bioactivities of Porcine Relaxin and Human Relaxin Do Not Differ in Mice and Rats (Shuangping Zhao, Hyung-Yul Lee, and O D Sherwood). 19. Tissue-Specific Effects of Relaxin on the Reproductive Tract of Neonatal Gilts (Wenbo Yan, Anne A. Wiley, Frank F. Bartol, And Carol A. Bagnell). 20. Increased Expression of the Relaxin Receptor (LGR7) in Human Endometrium during the Secretory Phase of the Menstrual Cycle (Courtney P. Bond, Laura J. Parry, Chrishan S. Samuel, Helen M. Gehring, Fiona L. Lederman, Peter A. W. Rogers, and Roger J. Summers). 21. Relaxin-Induced Angiogenesis in Ovary Contributes to Follicle Development (Kyoko Shirota, Kayoko Tateishi, Makoto Emoto, Toru Hachisuga, Masahide Kuroki, and Tatsuhiko Kawarabayashi). Part IIIA: Actions of Relaxin in Nonreproductive Tissues: Hemodynamic, Osmoregulatory, and Antifibrotic. 22. Role of Relaxin in Maternal Renal Vasodilation of Pregnancy (Kirk P. Conrad, Arun Jeyabalan, Leslie A. Danielson, Laurie J. Kerchner, And Jacqueline Novak). 23. Recombinant Human Relaxin (rhRLX) Modifies Systemic Arterial Properties in Conscious Rats Irrespective of Gender, but in a Biphasic Fashion (Dan O. Debrah, Kirk P. Conrad, Jackie Novak, Lee A. Danielson, And Sanjeev G. Shroff). 24. Renal Hemodynamic Effects of Relaxin in Humans (Marie Smith, John Davison, Kirk Conrad, And Lee Danielson). 25. The Relaxin Gene-Knockout Mouse: A Model of Progressive Fibrosis (Chrishan S. Samuel, Chongxin Zhao, Ross A.D. Bathgate, Xiao-Jun Du, Roger J. Summers, Edward P. Amento, Lesley L. Walker, Mary Mcburnie, Ling Zhao, And Geoffrey W. Tregear). 26. Relaxin Regulates Collagen Overproduction Associated with Experimental Progressive Renal Fibrosis (Chrishan S. Samuel, Ishanee Mookerjee, Rosemary Masterson, Geoffrey W. Tregear, And Tim D. Hewitson). 27. Relaxin Receptor Expression in Hepatic Stellate Cells and in Cirrhotic Rat Liver Tissue (Robert G. Bennett, Katrina J. Mahan, Martha J. Gentry-Nielsen, And Dean J. Tuma). 28. Relaxin Modulates Fibroblast Function, Collagen Production, and Matrix Metalloproteinase-2 Expression by Cardiac Fibroblasts (Ishanee Mookerjee, Elaine N. Unemori, Xiao-Jun Du, Geoffrey W. Tregear, and Chrishan S. Samuel). 29. Investigating the Role of Relaxin in the Regulation of Airway Fibrosis in Animal Models of Acute and Chronic Allergic Airway Disease (Ishanee Mookerjee, Mimi L.K. Tang, Natasha Solly, Geoffrey W. Tregear, And Chrishan S. Samuel). Part IIIB: Actions of Relaxin in Nonreproductive Tissues: Central Actions. 30. Localization of LGR7 Gene Expression in Adult Mouse Brain Using LGR7 Knock-out/LacZ Knock-in Mice: Correlation with LGR7 mRNA Distribution (Loretta Piccenna, Pei-Juan Shen, Sherie Ma, Tanya C. D. Burazin, Jan A. Gossen, Sietse Mosselman, Ross A. D. Bathgate, and Andrew L. Gundlach). 31. Localization of LGR7 (Relaxin Receptor) mRNA and Protein in Rat Forebrain: Correlation with Relaxin Binding Site Distribution (Tanya C.D. Burazin, Kelli J. Johnson, Sherie Ma, Ross A.D. Bathgate, Geoffrey W. Tregear, and Andrew L. Gundlach). 32. Insulin-Relaxin Family Peptide Signaling and Receptors in Mouse Brain Membranes and Neuronal Cells (Stefanie Ortinau, Feng Lin, John D. Wade, Geoffrey W. Tregear, Ross A.D. Bathgate, And Andrew L. Gundlach). 33. Central Effects of Long-Term Relaxin Expression in the Rat (Josh D. Silvertown, Russell Fraser, Roman S. Poterski, Brad Geddes, and Alastair J.S. Summerlee). 34. Relaxin Pretreatment Decreases Infarct Size in Male Rats after Middle Cerebral Artery Occlusion (Brian C. Wilson, Peter Milne, And Tarek M. Saleh). 35. Relaxin Inhibits Central Angiotensin II Expression in Killifish: A Central Osmoregulatory Role for Relaxin and Angiotensin II in the Killifish Fundulus heteroclitus (Adwoa Amamoo and Brian C. Wilson). Part IVA: Relaxin-Induced Signal Transduction: Interaction of Relaxin and Steroid Signaling. 36. New Insight into the Transcriptional Regulation of Vascular Endothelial Growth Factor Expression in the Endometrium by Estrogen and Relaxin: Robert D. Koos, Armina A. Kazi, Mark S. Roberson, and Jenny M. Jones). 37. Effects of Relaxin on Neonatal Porcine Uterine Growth and Development: Carol A. Bagnell, Wenbo Yan, Anne A. Wiley, And Frank F. Bartol). 38. The Pregnancy Hormone Relaxin Binds to and Activates the Human Glucocorticoid Receptor: Thomas Dschietzig, Cornelia Bartsch, Michael Greinwald, Gert Baumann, and Karl Stangl). Part IVB: Relaxin-Induced Signal Transduction: Relaxin Stimulates Multiple Signal Transduction Pathways. 39. Relaxin Stimulates Multiple Signaling Pathways: Activation of cAMP, PI3K, and PKC in THP-1 Cells (Carmen W. Dessauer and Bao T. Nguyen). 40. Relaxin Signaling from Natural Receptors (Richard Ivell, Ravinder Anand-Ivell, and Olaf Bartsch). 41. Signal Switching after Stimulation of LGR7 Receptors by Human Relaxin 2 (Michelle L. Halls, Ross A. Bathgate, and Roger J. Summers). 42. Signaling Pathways of the LGR7 and LGR8 Receptors Determined by Reporter Genes (Michelle L. Halls, Ross A. Bathgate, Peter J. Roche, and Roger J. Summers). 43. Relaxin Stimulates cAMP Production in MCF-7 Cells upon Overexpression of Type V Adenylyl Cyclase (Bao T. Nguyen and Carmen W. Dessauer). 44. Pathways Used by Relaxin to Regulate Myometrial Phospholipase C (Miao Zhong, Chun-Ying Ku, and Barbara M. Sanborn). 45. A Novel, Adenylate Cyclase, Signaling Mechanism of Relaxin H2 Action (Alexander Shpakov, Marianna Pertseva, Ludmila Kuznetsova, and Svetlana Plesneva). 46. Relaxin Restores Altered Ileal Spontaneous Contractions in Dystrophic (mdx) Mice (Maria Caterina Baccari, Franco Calamai, Laura Chiappini, Maria Giuliana Vannucchi, and Daniele Bani). 47. Effects of Relaxin on Vascular Smooth Muscle and Endothelial Cells in Normotensive and Hypertensive Rats (Paola Failli, Silvia Nistri, Luca Mazzetti, Laura Chiappini, and Daniele Bani). 48. Relaxin Induces Matrix Metalloproteinase-9 through Activation of Nuclear Factor Kappa B in Human THP-1 Cells (Teh-Yuan Ho and Carol A. Bagnell). 49. Does Human Relaxin-2 Affect Peripheral Blood Mononuclear Cells to Increase Inflammatory Mediators in Pathologic Bone Loss?: P Kristiansson, C Holding, S Hughes, and D Haynes). 50. Demonstration of Upregulated H2 Relaxin mRNA Expression during Neuroendocrine Differentiation of LNCaP Prostate Cancer Cells and Production of Biologically Active Mammalian Recombinant 6 Histidine-Tagged H2 Relaxin (Kevin A. Figueiredo, Jodie B. Palmer, Alice L. Mui, Colleen C. Nelson, and Michael E. Cox). 51. Is Relaxin a Calcium Transporter/Buffer? (Phillip A. Fields). 52. Responses of GPCR135 to Human Gene 3 (H3) Relaxin in CHO-K1 Cells Determined by Microphysiometry (Emma T. Van Der Westhuizen, Patrick M. Sexton, Ross A. D. Bathgate, and Roger J. Summers). Part VA: Clinical Aspects of Relaxin: Pregnancy. 53. Human Decidual Relaxin and Preterm Birth (Gillian D. Bryant-Greenwood, Sandra Y. Yamamoto, Kimberly M. Lowndes, Lisa E. Webster, Simone S. Parg, Aaron Amano, Erika E. Bullesbach, Christian Schwabe, and Lynnae K. Millar). 54. Mechanisms of Relaxin-Mediated Premature Birth (Gerson Weiss and Laura T. Goldsmith). 55. Clinical Use of Relaxin to Facilitate Birth: Reasons for Investigating the Premise (Hyung-Yul Lee, Shuangping Zhao, P A Fields, and O D Sherwood). 56. Relaxin Concentrations in Serum and Urine of Endangered Species: Correlations with Physiologic Events and Use As a Marker of Pregnancy (Bernard G. Steinetz, Janine L. Brown, Terri L. Roth, and Nancy Czekala). Part VB: Clinical Aspects of Relaxin: Connective Tissue. 57. Use of Relaxin in Orthodontics (Dennis R. Stewart, Paul Sherick, Susan Kramer, and Peter Breining). 58. Does Human Relaxin Accelerate Orthodontic Tooth Movement in Rats? (Zi Jun Liu, Gregory J. King, Gao Man Gu, Ja Young Shin, and Dennis R. Stewart). 59. The Use of Relaxin Improves Healing in Injured Muscle (Y Li, S Negishi, M Sakamoto, A Usas, and J Huard). 60. Photonic Monitoring in Real Time of Vascular Endothelial Growth Factor Receptor 2 Gene Expression under Relaxin-Induced Conditions in a Novel Murine Wound Model (Peter L. Ryan, Ramey C. Youngblood, Jane Harvill, and Scott T. Willard). 61. Relaxin of Prostatic Origin Might Be Linked to Perineal Hernia Formation in Dogs (Gert W. Niebauer, Sarina Shibly, Monika Seltenhammer, Armin Pirker, and Sabine Brandt). Part VC: Clinical Aspects of Relaxin: Ischemia/Allergic Response/Cancer. 62. Basic Progress and Future Therapeutic Perspectives of Relaxin in Ischemic Heart Disease (Daniele Bani, Silvia Nistri, Tatiana Bani Sacchi, and Mario Bigazzi). 63. Human Recombinant Relaxin Reduces Heart Injury and Improves Ventricular Performance in a Swine Model of Acute Myocardial Infarction (Avio-Maria Perna, Emanuela Masini, Silvia Nistri, Tatiana Bani Sacchi, Mario Bigazzi, and Daniele Bani). 64. Relaxin as an Additional Protective Substance in Preserving and Reperfusion Solution for Liver Transplantation, Shown in a Model of Isolated Perfused Rat Liver (Markus U. Boehnert, Heidegard Hilbig, and Franz P. Armbruster). 65. Myocardial Relaxin Counteracts Hypertrophy in Hypertensive Rats (Thomas Dschietzig, Cornelia Bartsch, Till Kinkel, Gert Baumann, and Karl Stangl). 66. Relaxin Favors the Morphofunctional Integration between Skeletal Myoblasts and Adult Cardiomyocytes in Coculture (Lucia Formigli, Fabio Francini, Laura Chiappini, Sandra Zecchi-Orlandini, and Daniele Bani). 67. Relaxin Adenylyl Cyclase System of Pregnant Women with Diabetes: Functional Defects in Insulin and Relaxin Adenylyl Cyclase Signaling Systems in Myometrium of Pregnant Women with Type 1 Diabetes (Ludmila Kuznetsova, Svetlana Plesneva, Alexander Shpakov, and Marianna Pertseva). 68. Human Medullary Thyroid Carcinoma: A Source and Potential Target for Relaxin-Like Hormones (T Klonisch, Tarek Mustafa, Joanna Bialek, Yvonne Radestock, Hans-Jürgen Holzhausen, Henning Dralle, Cuong Hoang-Vu, and Sabine Hombach-Klonisch). 69. Relaxin Downregulates the Calcium Binding Protein S100A4 in MDA-MB-231 Human Breast Cancer Cells (Yvonne Radestock, Cuong Hoang-Vu, and Sabine Hombach-Klonisch). 70. Relaxin Does Not Influence the Growth of Human Cervical Adenocarcinoma (HeLa) Cells in Culture (Young Shin Rho and Gyesik Min). 71. Effects of Relaxin in a Model of Rat Adjuvant-Induced Arthritis (Karen Santora, Cordelia Rasa, Denise Visco, Bernard Steinetz, and Carol Bagnell). Part VI: Physiologic Roles of INSL3. 72. Insulin-Like Factor 3: Where Are We Now? (Richard Ivell, Stefan Hartung, and Ravinder Anand-Ivell). 73. Insulin-Like Factor 3: A Novel Circulating Hormone of Testicular Origin in Humans (Alberto Ferlin and Carlo Foresta). 74. Immunohistochemical Localization of Relaxin-Like Factor/Insulin-Like Peptide-3 in the Bovine Corpus Luteum (Nicole Nichols, Hilary Binta, Phillip A. Fields, Maarten Drost, Shou-Mei Chang, Richard Ivell, and Michael J. Fields). 75. Restricted Expression of LGR8 in Intralaminar Thalamic Nuclei of Rat Brain Suggests a Role in Sensorimotor Systems (Pei-Juan Shen, Ping Fu, Kevin D. Phelan, Daniel J. Scott, Sharon Layfield, Geoffrey W. Tregear, Ross A.D. Bathgate, and Andrew L. Gundlach). 76. Detection, Localization, and Action of the INSL3 Receptor, LGR8, in Rat Kidney (Ping Fu, Pei-Juan Shen, Chong-Xin Zhao, Daniel J. Scott, Chrishan S. Samuel, John D. Wade, Geoffrey W. Tregear, Ross A.D. Bathgate, and Andrew L. Gundlach). Part VII: Evolution of Signaling Systems in Relaxin Family Peptides. 77. Evolution of the Signaling System in Relaxin-Family Peptides (Sheau Yu Teddy Hsu, Jenia Semyonov, Jae-Il Park, and Chia Lin Chang). 78. Evolution of the Relaxin-Like Peptide Family: From Neuropeptide to Reproduction (Tracey N. Wilkinson, Terry P. Speed, Geoffrey W. Tregear, and Ross A.D. Bathgate). 79. Coevolution of the Relaxin-Like Peptides and Their Receptors (Tracey N. Wilkinson, Terence P. Speed, Geoffrey W. Tregear, and Ross A.D. Bathgate)