Relaxin is a protein hormone of about 6000 Da, first described in 1926 by Frederick Hisaw.
The relaxin family peptide hormones belong to the insulin superfamily and consists of seven peptides of high structural but low sequence similarity; relaxin-1 (RLN1), 2 (RLN2) and 3 (RLN3), and the insulin-like (INSL) peptides, INSL3, INSL4, INSL5 and INSL6. The functions of relaxin-3, INSL4, INSL5, and INSL6 remain uncharacterised.
Synthesis
In the female, relaxin is produced by the corpus luteum of the ovary, the breast and, during pregnancy, also by the placenta, chorion, and decidua. In the male, it is produced in the prostate and is present in human semen.
Structure
Structurally, relaxin is a heterodimer of two peptide chains of 24 and 29 amino acids linked by three disulfide bridges, and it appears related to insulin.
Relaxin is produced from its prohormone, "prorelaxin", by post-translational proteolytic cleavage of its signal peptide and C domain peptide.
Function in humans
Reproduction
In females, relaxin is produced mainly by the corpus luteum, in both pregnant and nonpregnant females. Relaxin levels rise to a peak within approximately 14 days of ovulation, and then decline in the absence of pregnancy, resulting in menstruation. Relaxin may be involved in the vital process of decidualisation, working alongside steroid hormones to allow the endometrium to prepare for implantation. During the first trimester of pregnancy, levels rise and additional relaxin is produced by the decidua. Blood plasma levels of relaxin peak during the first trimester (8-12 weeks) at 1.2 ng/mL and subsequently drop following demise of the corpus luteum. In pregnancy, relaxin mediates the hemodynamic changes that occur such as increased cardiac output and increased renal blood flow. It also relaxes other pelvic ligaments in the lower reproductive tract.
In males, relaxin enhances motility of sperm in semen. Also, relaxin is found in higher than normal concentrations in the ejaculate of men who were born without their vas deferens and seminal vesicles.
Cardiovascular function
In the cardiovascular system, relaxin is secreted by the heart and functions as a vasodilator mainly through the nitric oxide pathway. Other mechanisms include activation of NFκB leading to vascular endothelial growth factor (VEGF), activation of PI3K/Akt-associated signaling pathways, and matrix metalloproteinases transcription. In ex vivo experiments using subcutaneous resistance arteries, relaxin has shown to be a powerful endothelium-dependent vasodilator.
Via upregulation of VEGF, relaxin also plays a key role in blood vessel formation (angiogenesis) during pregnancy, tumour development or ischaemic wounds.
Function in other animals
Reproduction
In animals, relaxin widens the pubic bone and facilitates labor; it also softens the cervix (cervical ripening), and softens the pubic symphysis in rat and guinea pig models. Thus, for a long time, relaxin was looked at as a pregnancy hormone. However, its significance may reach much further. Relaxin may affect collagen metabolism, inhibiting collagen synthesis and enhancing its breakdown by increasing matrix metalloproteinases. It also enhances angiogenesis and is a potent renal vasodilator.
In horses (Equus caballus), relaxin is also an important hormone involved in pregnancy; however, before pregnancy occurs, relaxin is expressed by ovarian structures during the oestrous cycle. Prior to ovulation, relaxin will be produced by ovarian stromal cells, which will promote secretion of gelatinases and tissue inhibitors of metalloproteinases. These enzymes will then aid the process of ovulation, which will lead to the release of a developed follicle into the fallopian tube. Furthermore, granular and theca cells in the follicles will express relaxin in increasing levels depending on their size. During early pregnancy, the preimplantation conceptus will express relaxin, which will promote angiogenesis in the endometrium by up-regulating VEGF. This will allow the endometrium to prepare for implantation. In horses alone, the embryo in the uterus will express relaxin mRNA at least 8 days after ovulation. Then as the conceptus develops expression will increase, which is likely to promote embryo development.