Relaxin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

of about 6000 Da, first described in 1926 by Frederick Hisaw. The

relaxin family peptide hormones Relaxin family peptide hormones in humans are represented by seven members: three relaxin-like (RLN) and four insulin-like (INSL) peptides: RLN1, RLN2, Relaxin-3, RNL3, INSL3, INSL4, INSL5, INSL6. This subdivision into two classes (RLN and I ...

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 Insulin-like 3 is a protein that in humans is encoded by the ''INSL3'' gene. Function The protein encoded by this gene is an insulin like hormone produced mainly in gonadal tissues in males and females. Studies of the mouse counterpart sugges ...

, 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 The corpus luteum (Latin for "yellow body"; : corpora lutea) is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is the ...

of the

ovary The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/ oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are end ...

, the

breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...

and, during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

, also by the

placenta The placenta (: placentas or placentae) is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas, and waste exchange between ...

chorion The chorion is the outermost fetal membrane around the embryo in mammals, birds and reptiles (amniotes). It is also present around the embryo of other animals, like insects and molluscs. Structure In humans and other therian mammals, the cho ...

, and

decidua The decidua is the modified mucosal lining of the uterus (that is, modified endometrium) that forms every month, in preparation for pregnancy. It is shed off each month when there is no fertilized egg to support. The decidua is under the influe ...

. In the male, it is produced in the prostate and is present in human semen.

Structure

Structurally, relaxin is a

heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

of two peptide chains of 24 and 29

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s linked by three

disulfide In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inorg ...

bridges, and it appears related to

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

. Relaxin is produced from its

prohormone A prohormone is a committed precursor of a hormone consisting of peptide hormones synthesized together that has a minimal hormonal effect by itself because of its expression-suppressing structure, often created by protein folding and binding addit ...

, "prorelaxin", by

post-translational In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA int ...

proteolytic cleavage Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

of its

signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16–30 amino acids long) present at the ...

and C domain peptide.

Function in humans

Reproduction

In females, relaxin is produced mainly by the

, in both pregnant and nonpregnant females. Relaxin levels rise to a peak within approximately 14 days of

ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...

, and then decline in the absence of pregnancy, resulting in

menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and Mucous membrane, mucosal tissue from the endometrium, inner lining of the uterus through the vagina. The menstrual cycle is characterized ...

. Relaxin may be involved in the vital process of decidualisation, working alongside

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wit ...

s to allow the

endometrium The endometrium is the inner epithelium, epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The funct ...

to prepare for implantation. During the

first trimester Pregnancy is the time during which one or more offspring gestates inside a woman's uterus. A multiple pregnancy involves more than one offspring, such as with twins. Conception usually occurs following vaginal intercourse, but can also ...

of pregnancy, levels rise and additional relaxin is produced by the

Blood plasma Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...

levels of relaxin peak during the

(8-12 weeks) at 1.2 ng/mL and subsequently drop following demise of the

. In pregnancy, relaxin mediates the

hemodynamic Hemodynamics or haemodynamics are the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms of autoregulation, just as hydraulic circuits are controlled by control systems. The hemodynamic response continuously ...

changes that occur such as increased

cardiac output In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: tha ...

and increased

renal blood flow In renal physiology, renal blood flow (RBF) is the volume of blood delivered to the kidneys per unit time. In humans, the kidneys together receive roughly 20 - 25% of cardiac output, amounting to 1.2 - 1.3 L/min in a healthy adult. It passes about ...

. Relaxin is believed to relax the uterine muscle and to loosen the ligaments holding the pelvic bones together, in order to prepare the birth canal for the birth. It may cause a woman to feel that other ligaments are looser, such as in the shoulders, knees, hips, and ankles. 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 The vas deferens (: vasa deferentia), ductus deferens (: ductūs deferentes), or sperm duct is part of the male reproductive system of many vertebrates. In mammals, spermatozoa are produced in the seminiferous tubules and flow into the epididyma ...

and

seminal vesicles The seminal vesicles (also called vesicular glands or seminal glands) are a pair of convoluted tubular accessory glands that lie behind the urinary bladder of male mammals. They secrete fluid that largely composes the semen. The vesicles are 5 ...

Cardiovascular function

In the

cardiovascular system In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

, relaxin is secreted by the

heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...

and functions as a vasodilator mainly through the

nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...

pathway. Other mechanisms include activation of NFκB leading to

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

(VEGF), activation of PI3K/Akt-associated signaling pathways, and

matrix metalloproteinases Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...

transcription. In ''

ex vivo refers to biological studies involving tissues, organs, or cells maintained outside their native organism under controlled laboratory conditions. By carefully managing factors such as temperature, oxygenation, nutrient delivery, and perfusi ...

'' 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 Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...

) during pregnancy, tumour development or ischaemic wounds.

Function in other animals

Reproduction

In animals, relaxin widens the

pubic bone In vertebrates, the pubis or pubic bone () forms the lower and anterior part of each side of the hip bone. The pubis is the most forward-facing (ventral and anterior) of the three bones that make up the hip bone. The left and right pubic bones ar ...

and facilitates

labor Labour or labor may refer to: * Childbirth, the delivery of a baby * Labour (human activity), or work ** Manual labour, physical work ** Wage labour, a socioeconomic relationship between a worker and an employer ** Organized labour and the labour ...

; it also softens the

cervix The cervix (: cervices) or cervix uteri is a dynamic fibromuscular sexual organ of the female reproductive system that connects the vagina with the uterine cavity. The human female cervix has been documented anatomically since at least the time ...

(cervical ripening), and softens the

pubic symphysis The pubic symphysis (: symphyses) is a secondary cartilaginous joint between the left and right superior rami of the pubis of the hip bones. It is in front of and below the urinary bladder. In males, the suspensory ligament of the penis attache ...

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 Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

metabolism, inhibiting collagen synthesis and enhancing its breakdown by increasing

matrix metalloproteinase Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...

s. It also enhances

and is a potent renal

vasodilator Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wal ...

. In horses (''Equus caballus''), relaxin is also an important hormone involved in

; however, before pregnancy occurs, relaxin is expressed by ovarian structures during the

oestrous cycle The estrous cycle (, originally ) is a set of recurring physiological changes induced by reproductive hormones in females of mammalian subclass Theria. Estrous cycles start after sexual maturity in females and are interrupted by anestrous phases ...

. Prior to

, relaxin will be produced by ovarian

stromal Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine muco ...

cells, which will promote secretion of

gelatinase Gelatinases are enzymes capable of degrading gelatin through hydrolysis, playing a major role in degradation of extracellular matrix and tissue remodeling. Gelatinases are a type of matrix metalloproteinase (MMP), a family of enzymes that depend on ...

s 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 A conceptus (from Latin Latin ( or ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally spoken by the Latins (Italic tribe), Latins in Latium (now known as Lazio), ...

will express relaxin, which will promote

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. 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. 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. From 80 day of

gestation Gestation is the period of development during the carrying of an embryo, and later fetus, inside viviparous animals (the embryo develops within the parent). It is typical for mammals, but also occurs for some non-mammals. Mammals during pregn ...

onwards, relaxin levels will increase in the mare's serum with levels peaking in late gestation. Moreover, the pattern of relaxin expression will follow the expression of

oestrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three m ...

, however, there is not yet a known link between these two hormones. During labour, there is a spike in relaxin 3–4 hours before delivery, which is involved in

myometrial The myometrium is the middle layer of the uterine wall, consisting mainly of uterine smooth muscle cells (also called uterine myocytes) but also of supporting stromal and vascular tissue. Its main function is to induce uterine contractions. Stru ...

relaxation and softening of the pelvic ligaments to aid preparation of the birth canal for the delivery of the horse foetus. 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. In addition, if the mare undergoes an

abortion Abortion is the early termination of a pregnancy by removal or expulsion of an embryo or fetus. Abortions that occur without intervention are known as miscarriages or "spontaneous abortions", and occur in roughly 30–40% of all pregnan ...

then the relaxin levels will decline as the placenta ceases to function.

Cardiovascular function

Relaxin has been shown to relax

vascular smooth muscle cells Vascular smooth muscle is the type of smooth muscle that makes up most of the walls of blood vessels. Structure Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood v ...

and increase nitric oxide production in rat

endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

, thus playing a role in regulation of cardiovascular function by dilating systemic resistance arteries. Relaxin increases the rate and force of cardiac contraction in rat models and has been found to promote maturation of

cardiomyocytes Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of ...

in mice. Several animal studies have found relaxin to have a cardioprotective function against

ischaemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...

and

reperfusion injury Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is the tissue damage caused when blood supply returns to tissue ('' re-'' + ''perfusion'') after a period of ischemia or lack of oxygen (anoxia or hy ...

, by reducing cellular damage, via anti-

apoptotic Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes ( morphology) and death. These ...

and

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...

effects. Relaxin has been shown to reduce

cardiac fibrosis Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. Fibrotic c ...

in animal models by inhibiting cardiac

fibroblasts A fibroblast is a type of biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibrobla ...

secreting

and stimulating

. In the European rabbit (''

Oryctolagus cuniculus The European rabbit (''Oryctolagus cuniculus'') or coney is a species of rabbit native to the Iberian Peninsula (Spain, Portugal and Andorra) and southwestern France. It is the only extant species in the genus '' Oryctolagus''. The European ra ...

''), relaxin is associated with squamous differentiation and is expressed in tracheobronchial epithelial cells as opposed to being involved with reproduction.

Receptors

Relaxin interacts with the

relaxin receptor The relaxin receptors are a subclass of four closely related G protein-coupled receptors (GPCR) that bind relaxin peptide hormones. Below is list of human relaxin receptors, their endogenous peptide hormones, and what downstream enzymes are a ...

LGR7 (

RXFP1 Relaxin/insulin-like family peptide receptor 1, also known as RXFP1, is a human G protein coupled receptor that is one of the relaxin receptors. It is a rhodopsin-like GPCR which is unusual in this class as it contains a large extracellular bind ...

) and LGR8 ( RXFP2), which belong to the

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...

superfamily. They contain a heptahelical

transmembrane domain A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in ...

and a large glycosylated ectodomain, distantly related to the receptors for the glycoproteohormones, such as the LH-receptor or FSH-receptor. Relaxin receptors have been found in the

smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...

, the

connective tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...

, and central and

autonomous nervous system The autonomic nervous system (ANS), sometimes called the visceral nervous system and formerly the vegetative nervous system, is a division of the nervous system that operates internal organs, smooth muscle and glands. The autonomic nervous system ...

Disorders

Women who have been on relaxin treatment during unrelated clinical trials have experienced heavier bleeding during their menstrual cycle, suggesting that relaxin levels could play a role in

abnormal uterine bleeding Abnormal uterine bleeding is vaginal bleeding from the uterus that is abnormally frequent, lasts excessively long, is heavier than normal, or is irregular. The term "dysfunctional uterine bleeding" was used when no underlying cause was presen ...

. However, more research is needed to confirm relaxin as a direct cause. A lower expression of relaxin has been found amongst women who have

endometriosis Endometriosis is a disease in which Tissue (biology), tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus. It occurs in women and a limited number of other female mammals. Endomet ...

. The research in this area is limited and more studying of relaxin's contribution could contribute greatly to the understanding of endometriosis. Specific disorders related to relaxin have not been heavily described, yet a link to

scleroderma Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...

and

fibromyalgia Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...

has also been suggested.

Pregnancy

It is possible that relaxin in the

could be a contributing factor to inducing labour in humans and therefore serum relaxin levels during pregnancy have been linked to

premature birth Preterm birth, also known as premature birth, is the birth of a baby at fewer than 37 weeks gestational age, as opposed to full-term delivery at approximately 40 weeks. Extreme preterm is less than 28 weeks, very early preterm birth is betwee ...

Pharmacological targets

Recombinant forms of human relaxin-2 such as volenrelaxin (LY3540378) and serelaxin (RLX030) have been developed as investigational drugs. It is suggested that relaxin could be used as a therapeutic target when it comes to gynaecological disorders.

Evolution

Relaxin 1 and relaxin 2 arose from the duplication of a proto-RLN gene between 44.2 and 29.6 million years ago in the last common ancestor of

catarrhine The parvorder Catarrhini (known commonly as catarrhine monkeys, Old World anthropoids, or Old World monkeys) consists of the Cercopithecoidea and apes (Hominoidea). In 1812, Geoffroy grouped those two groups together and established the name Ca ...

primates. The duplication that led to RLN1 and RLN2 is thought to have been a result of positive selection and convergent evolution at the nucleotide level between the relaxin gene in

New World monkeys New World monkeys are the five families of primates that are found in the tropical regions of Mexico, Central and South America: Callitrichidae, Cebidae, Aotidae, Pitheciidae, and Atelidae. The five families are ranked together as the Ceboide ...

and the RLN1 gene in

apes Apes (collectively Hominoidea ) are a superfamily of Old World simians native to sub-Saharan Africa and Southeast Asia (though they were more widespread in Africa, most of Asia, and Europe in prehistory, and counting humans are found glo ...

. As a result,

Old World monkeys Old World monkeys are primates in the family (biology), family Cercopithecidae (). Twenty-four genus, genera and 138 species are recognized, making it the largest primate family. Old World monkey genera include baboons (genus ''Papio''), red colo ...

, a group that includes the subfamilies colobines and cercopithecines, have lost the RLN1 paralog, but apes have retained both the RLN1 and the RLN2 genes.

References

External links

* * {{Authority control Peptide hormones Hormones of the ovary Hormones of the placenta Hormones of the pregnant female Human female endocrine system

Synthesis

Structure

Function in humans

Reproduction

Cardiovascular function

Function in other animals

Reproduction

Cardiovascular function

Receptors

Disorders

Pregnancy

Pharmacological targets

Evolution

See also

References

External links