Relaxin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

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, RNL3, INSL3, INSL4, INSL5, INSL6. This subdivision into two classes (RLN and INSL) is ...

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 Relaxin-3 is a neuropeptide that was discovered in 2001, and which is highly conserved in species ranging from flies, fish, rodents and humans. Relaxin-3 is a member and ancestral gene of the relaxin family of peptides, which includes the namesa ...

), 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 Early placenta insulin-like peptide is a protein that in humans is encoded by the ''INSL4'' gene. INSL4 encodes the insulin-like 4 protein, a member of the insulin superfamily. INSL4 encodes a precursor that undergoes post-translational cleavage ...

INSL5 Insulin-like peptide 5 (INSL5) is a protein that in humans is encoded by the ''INSL5'' gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generatio ...

and

INSL6 Insulin like 6 is a protein that in humans is encoded by the INSL6 gene. Function The protein encoded by this gene contains a classical signature of the insulin superfamily and is significantly similar to relaxin and relaxin-like factor. Th ...

. 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"; plural 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 t ...

of the

ovary The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...

, the

breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and sec ...

and, during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

, also by the

placenta The placenta 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 the physically separate mate ...

chorion The chorion is the outermost fetal membrane around the embryo in mammals, birds and reptiles (amniotes). It develops from an outer fold on the surface of the yolk sac, which lies outside the zona pellucida (in mammals), known as the vitell ...

, 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 fertilised egg to support. The decidua is under the influen ...

. 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 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 ''dimer'' ha ...

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 hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

s linked by

disulfide In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

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 ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism ...

. 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 additi ...

, "prorelaxin", by

post-translational Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosom ...

proteolytic cleavage Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...

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 N-te ...

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 the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...

, 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 mucosal tissue from the inner lining of the uterus through the vagina. The menstrual cycle is characterized by the rise and fall of ...

. 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). Withi ...

s to allow the

endometrium The endometrium is the inner 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 functional layer ...

to prepare for implantation. During the

first trimester Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

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

Blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the int ...

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 mo ...

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: th ...

and increased

renal blood flow In the physiology of the kidney, renal blood flow (RBF) is the volume of blood delivered to the kidneys per unit time. In humans, the kidneys together receive roughly 25% of cardiac output, amounting to 1.2 - 1.3 L/min in a 70-kg adult male. It ...

. It also relaxes other pelvic ligaments in the lower reproductive tract. In males, relaxin enhances motility of sperm in semen.

Cardiovascular function

In the

cardiovascular system The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

, relaxin is secreated by the

heart The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...

and functions as a vasodialator mainly through the

nitric oxide Nitric oxide (nitrogen oxide 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 denoted by a dot in its ...

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 ...

transcription. In ''

ex vivo ''Ex vivo'' (Latin: "out of the living") literally means that which takes place outside an organism. In science, ''ex vivo'' refers to experimentation or measurements done in or on tissue from an organism in an external environment with minimal ...

'' 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 by processes of sprouting and splittin ...

) during pregnancy, tumour development or ischaemic wounds.

Function in other animals

Reproduction

In animals, relaxin widens the

pubic bone In vertebrates, the pubic region ( la, pubis) is the most forward-facing ( ventral and anterior) of the three main regions making up the coxal bone. The left and right pubic regions are each made up of three sections, a superior ramus, inferior ...

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 la ...

; it also softens the

cervix The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during ...

(cervical ripening), and softens the

pubic symphysis The pubic symphysis 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 attaches to the pubi ...

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 found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...

metabolism, inhibiting collagen synthesis and enhancing its breakdown by increasing matrix metalloproteinases. It also enhances

and is a potent renal

vasodilator Vasodilation 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. The process is the opposite of vasoconstrictio ...

. 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. 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 mucos ...

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 A conceptus (from Latin: ''concipere'' to conceive) is an embryo and its appendages (adnexa), the associated membranes, placenta, and umbilical cord; the products of conception or, more broadly, "the product of conception at any point between fert ...

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 pr ...

onwards, relaxin levels will increase in the mare's

serum Serum may refer to: * Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity * Serous fluid, any clear bodily fluid *Truth serum, a drug that is likely to mak ...

with levels peaking in late gestation. Moreover, the pattern of relaxin expression will follow the expression of

oestrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal activ ...

, 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. Struc ...

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 termination of a pregnancy by removal or expulsion of an embryo or fetus. An abortion that occurs without intervention is known as a miscarriage or "spontaneous abortion"; these occur in approximately 30% to 40% of pre ...

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

Cardiovascular function

Relaxin has been shown to relax vascular smooth muscle cells and increase nitric oxide production in rat

endothelial cells The endothelium 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 rest of the vessel ...

, 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, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...

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 grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...

and

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

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 ...

in animal models by inhibiting cardiac

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...

secreting

and stimulating matrix metalloproteinase. In the European rabbit (''

Oryctolagus cuniculus The European rabbit (''Oryctolagus cuniculus'') or coney is a species of rabbit native to the Iberian Peninsula (including Spain, Portugal, and southwestern France), western France, and the northern Atlas Mountains in northwest Africa. It has ...

''), 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 LGR7 ( RXFP1) 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 p ...

superfamily. They contain a heptahelical

transmembrane domain A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bi ...

and a large glycosylated ectodomain, distantly related to the receptors for the glycoproteohormones, such as the LH-receptor or

FSH-receptor The follicle-stimulating hormone receptor or FSH receptor (FSHR) is a transmembrane receptor that interacts with the follicle-stimulating hormone (FSH) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the horm ...

. Relaxin receptors have been found in the

smooth muscle Smooth muscle is an involuntary non- striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit ...

, the

connective tissue Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...

, and central and autonomous 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 (AUB), also known as (AVB) or as atypical vaginal bleeding, is vaginal bleeding from the uterus that is abnormally frequent, lasts excessively long, is heavier than normal, or is irregular. The term dysfunctional uterin ...

. 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 of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, fa ...

. 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 medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hyp ...

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 between ...

Pharmacological targets

A recombinant form of human relaxin-2 has been developed as investigational drug RLX030 ( serelaxin). 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 , catarrhine monkeys, Old World anthropoids, or Old World monkeys, consisting of the Cercopithecoidea and apes (Hominoidea). In 1812, Geoffroy grouped those two groups together and established the name Catarrhini, "Old ...

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 Ceboidea ...

and the RLN1 gene in

apes Apes (collectively Hominoidea ) are a clade of Old World simians native to sub-Saharan Africa and Southeast Asia (though they were more widespread in Africa, most of Asia, and as well as Europe in prehistory), which together with its sister g ...

. As a result,

Old World monkeys Old World monkey is the common English name for a family of primates known taxonomically as the Cercopithecidae (). Twenty-four genera and 138 species are recognized, making it the largest primate family. Old World monkey genera include babo ...

, 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