Relaxin

In females, relaxin is produced mainly by the corpus luteum, in both pregnant and nonpregnant females.[1] Relaxin levels rise to a peak within approximately 14 days of ovulation, and then decline in the absence of pregnancy, resulting in menstruation.[9] Relaxin may be involved in the vital process of decidualisation, working alongside steroid hormones to allow the endometrium to prepare for implantation.[10] 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.[11] In pregancy, relaxin mediates the hemodynamic changes that occur such as increased cardiac output and increased renal blood flow.[12] It also relaxes other pelvic ligaments in the lower reproductive tract.[13]

In males, relaxin enhances motility of sperm in semen.[14]

In the cardiovascular system, relaxin is secreated by the heart[15] and functions as a vasodialator 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,[16] and matrix metalloproteinases transcription.[17] In ex vivo experiments using subcutaneous resistance arteries, relaxin has shown to be a powerful endothelium-dependent vasodilator.[15][18]

Via upregulation of VEGF, relaxin also plays a key role in blood vessel formation (angiogenesis) during pregnancy, tumour development or ischaemic wounds.[19]

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.[12] 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.[20] 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.[21] 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.[21] Furthermore, granular and theca cells in the follicles will express relaxin in increasing levels depending on their size.[21] During early pregnancy, the preimplantation conceptus will express relaxin, which will promote angiogenesis in the endometrium by up-regulating VEGF.[21][22] 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.[21]

In addition to relaxin production by the horse embryo, the maternal placenta is the main source of relaxin production, whereas in most animals the main source of relaxin is the corpus luteum.[21] Placental trophoblast cells produce relaxin, however, the size of the placenta does not determine the level of relaxin production. This is seen because different breeds of horses show different relaxin levels.[23] From 80 day of gestation onwards, relaxin levels will increase in the mare's serum with levels peaking in late gestation.[23][24] Moreover, the pattern of relaxin expression will follow the expression of oestrogen, however, there is not yet a known link between these two hormones.[24] During labour, there is a spike in relaxin 3–4 hours before delivery, which is involved in myometrial relaxation and softening of the pelvic ligaments to aid preparation of the birth canal for the delivery of the horse foetus.[21][23] Following birth, the levels of relaxin will gradually decrease if the placenta is also delivered, however, if the placenta is retained in the mare then the levels will remain high.[23] In addition, if the mare undergoes an abortion then the relaxin levels will decline as the placenta ceases to function.[23]

Relaxin has been shown to relax vascular smooth muscle cells and increase nitric oxide production in rat endothelial cells, thus playing a role in regulation of cardiovascular function by dilating systemic resistance arteries.[17] Relaxin increases the rate and force of cardiac contraction in rat models and has been found to promote maturation of cardiomyocytes in mice.[19]

Several animal studies have found relaxin to have a cardioprotective function against ischaemia and reperfusion injury, by reducing cellular damage, via anti-apoptotic and anti-inflammatory effects. Relaxin has been shown to reduce cardiac fibrosis in animal models by inhibiting cardiac fibroblasts secreting collagen and stimulating matrix metalloproteinase.[19][17]

In the European rabbit (Oryctolagus cuniculus), relaxin is associated with squamous differentiation and is expressed in tracheobronchial epithelial cells as opposed to being involved with reproduction.[25]

It is possible that relaxin in the placenta could be a contributing factor to inducing labour in humans and therefore serum relaxin levels during pregnancy have been linked to premature birth.[27]