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Camerino, C. Oxytocin from the Uterus to the Heart. Encyclopedia. Available online: https://encyclopedia.pub/entry/44104 (accessed on 20 June 2024).
Camerino C. Oxytocin from the Uterus to the Heart. Encyclopedia. Available at: https://encyclopedia.pub/entry/44104. Accessed June 20, 2024.
Camerino, Claudia. "Oxytocin from the Uterus to the Heart" Encyclopedia, https://encyclopedia.pub/entry/44104 (accessed June 20, 2024).
Camerino, C. (2023, May 10). Oxytocin from the Uterus to the Heart. In Encyclopedia. https://encyclopedia.pub/entry/44104
Camerino, Claudia. "Oxytocin from the Uterus to the Heart." Encyclopedia. Web. 10 May, 2023.
Oxytocin from the Uterus to the Heart
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The research program on oxytocin started in 1895, when Oliver and Schafer reported that a substance extracted from the pituitary gland elevates blood pressure when injected intravenously into dogs. Dale later reported that a neurohypophysial substance triggers uterine contraction, lactation, and antidiuresis. Purification of this pituitary gland extracts revealed that the vasopressor and antidiuretic activity could be attributed to vasopressin, while uterotonic and lactation activity could be attributed to oxytocin. In 1950, the amino-acid sequences of vasopressin and oxytocin were determined and chemically synthesized. Vasopressin (CYFQNCPRG-NH2) and oxytocin (CYIQNCPLG-NH2) differ by two amino acids and have a disulfide bridge between the cysteine residues at position one and six conserved in all vasopressin/oxytocin-type peptides. This characterization of oxytocin led to the Nobel Prize awarded in 1955 to Vincent du Vigneaud.

oxytocin oxytocin receptor bone skeletal muscle heart

1. Introduction

Oxytocin (Oxt) is a nonapeptide mainly produced in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. Oxt in the brain and blood has extensive functions in both mental and physical activities. Oxt appears to be involved in the regulation of the three components of body composition: bone, fat, and muscle. Oxt effects include the regulation of energy and metabolism, appetite, and effects on the gastrointestinal system (GI), skeletal, and cardiac muscle [1].

2. Year—1955: Oxytocin Is First Discovered for Its Effects on Uterine Contractility but Expresses Sexual Dimorphism

2.1. Oxytocin in Women Health

Oxt functions are mediated by Oxtrs, and, although the uterus is the organ where Oxtrs are expressed at a higher density, Oxtrs are distributed in a wide spectrum of tissues with dramatic sexual dimorphism, meaning that Oxtrs are expressed in different density to assure an effect that is specific to sex and type of tissue. Mature Oxt and the carrier neurophysin are processed from the Oxt/neurophysin 1 prepropetide [2]. It seems that the predominant role of neurophysin is to target, package, and store Oxt within secretory granules prior to release [3]. Oxt is released both locally from somatodentrites from magnocellular Oxt neurons in SON and PVN, and distally at axon terminals within the neurohypophysis that originates from magnocellular PVN and SON. Back in 1955, Oxt was first identified for its effect on uterus contractility, and this discovery was awarded with the Nobel Prize for chemistry to Vincent du Vigneaud [4][5][6]. However, the fact that Oxt was first identified in the uterus does not mean that its functions are limited to this organ, although, for the first 50 years of its life, research was limited to it. Indeed, in both sexes, Oxt generally inhibits pain perception, is anorexigenic, and augments muscle tonicity, sexual activities, and aggressiveness. However, there are significant differences in Oxt levels and distribution of Oxtrs in men from women. Thus, Oxt functions in men are different from women, particularly in reproduction. In men, the reproductive functions are relatively simple [7]. In women, the reproductive functions involve the menstrual cycle, pregnancy, parturition, lactation, and menopause. This is why Oxt regulation of women’s health and disease is a unique topic of physiological and pathological studies. Indeed, women’s biological activities are regulated not only by the hypothalamic–pituitary–gonad (HPG) axis but also by Oxt. While Oxt commonly influences sexual behavior, production of sex steroids, and the maturation of gemmates of both sexes, it differently influences women’s health and disease at different reproductive stages because Oxt and Oxtrs are differently expressed in various organs, and these histological features allow Oxt to modulate body functions differently and with different patterns including neuromodulation, neurosecretion, endocrine, autocrine, and paracrine effects. Under the regulation of these extracellular and intracellular factors, Oxt neuronal activity and Oxt secretion can meet the demands of body activities in response to environmental changes. In mammals, Oxtrs have been identified in a broad spectrum of tissues, including the kidney, heart, thymus, pancreas, adipocytes, and other sites in addition to the central nervous system (CNS) [3][7]. Expression of Oxtrs in the hypothalamus, uterus, and mammary gland is stimulated by estrogens [8]. In females, Oxtrs are specifically localized in myoepithelial cells of the mammary glands and in the myometrium and endometrium of the uterus. Peripheral actions of Oxt are commonly associated with smooth muscle contraction, particularly within the female and male reproductive tracts [9]. In the brain and spinal cord, activation of Oxtrs is associated with a variety of mental activities such as social memory, pair bonding, maternal behavior, and aggression, as well as instinctive behaviors such as sexual activity, anxiety, feeding, and pain perception, all related to reproduction. By innervating median eminence and median preoptic area, Oxt can increase gonadotropin-releasing hormone (GnRH) release and the activity of the HPG axis [7][10]. By contrast, circulating and locally produced Oxt can influence body functions at cellular, tissue, and organ levels.

2.2. Oxytocin in Men and Women

Oxt extensively modulates body functions, although significant differences between males and females emerge. Sexual dimorphism of Oxt functions is based on expression levels of Oxt and Oxtrs. For instance, serum Oxt is significantly higher among women than men [11], making women more sensitive to Oxt reduction, which accounts for menstrual pain [11]. By contrast, Oxt binding sites in the ventromedial hypothalamus (VMH) and dorsal horns are significantly higher in males vs. females [7], which may contribute to the central regulatory actions of Oxt on feeding. Males also exhibit higher Oxtr levels in the medial amygdale irrespective of the reproductive status [12], which likely makes men less fearful facing stressful challenges because Oxt acting on the medial amygdale inhibits fear. Higher Oxtr levels in the nucleus accumbens are present at breeding males but not females [12], which makes paternal behaviors conditional [13] and more rewarding [7][14][15]. This sex dimorphism in the distribution of Oxt and Oxtrs sets a histological basis for gender specific functions and behavior. Oxt can extensively modulate body activities at peripheral sites and is a pivotal regulator of male reproductive functions, although, among all Oxt functions, the most dramatic sexual dimorphism is in reproduction. Oxt increases during sex arousal in males and females and in the CNS. Oxt from the PVN in the ventral tegmental area (VTA) initiates a pathway that involves activation of dopamine, glutamate, and other neurons in the VTA, triggering the motivational and rewarding aspects of sexual behavior [16]. Oxt release from Oxt neurons does not increase during pregnancy until the time shortly before parturition. Thus, the development of Oxt/Oxtr signaling is an adaptive response for maintaining the safety of pregnancy. However, increased Oxt synthesis and preterm Oxt release in the hypothalamus are necessary for the maturation of hypothalamic machinery that allows Oxt to be released in intermittent pulses during parturition and lactation [7]. Thus, Oxt actions during pregnancy highly match peripartum physiological demands. Plasma Oxt and nocturnal uterine activity increase progressively during late pregnancy and delivery [7]. This is associated with the effect of light/darkness on the pulsatile Oxt release [7], which determine the high incidence of parturition during the night. Regarding the lactation-associated health issue, it has been extensively accepted that normal breastfeeding can reduce the incidence of postpartum depression, maternal obesity, and diabetes. Oxt is necessary for these benefits of breastfeeding. Moreover, cardiovascular diseases increase dramatically in postmenopausal women. When estrogen production decreases, the activation of estrogen receptors on pre-autonomic PVN Oxt neurons is also weakened. As a result, Oxt regulation of the HPG axis is weakened. By contrast Oxt can protect the cardiovascular system by maintaining cardiovascular integrity, suppressing atherosclerotic alterations and coronary artery disease, and promoting regeneration and repair injuries [17]. Thus, Oxtr/Oxt protection is suppressed more strongly in the ischemic myocardium in females than males.

3. Year—2007: Oxytocin Is in Bone

3.1. In Vitro Studies

In early 2007, the anabolic effect of peripheral Oxt on bone was demonstrated. Bone cells express Oxtrs, and Oxt promotes osteoblast (OB) differentiation and function, leading to an increased bone formation with no effect on bone resorption and an improvement of bone microarchitecture. Oxt is synthesized by OB, and this synthesis is stimulated by estrogens. Animal studies demonstrate a direct action of Oxt on bone, as the systemic administration of Oxt prevents and reverses the bone loss induced by estrogen deficiency. Although Oxt is involved in bone formation in both sexes during development, Oxt treatment has no effect on male osteoporosis [15]. Bone mass is maintained by the balance between bone formation by OB and bone resorption by osteoclasts (OC). Oxt negatively modulates adipogenesis [18]. The anabolic action of Oxt appears to be related in part to a direct effect on its receptor expressed on OB [15]. Estrogens are known to stimulate Oxt synthesis in bone as in other tissues [3][19]. Estrogens positively stimulate Oxt production by OB, through activation of the MAP kinase/ERK pathway and Oxtr expression by a genomic mechanism of action [15]. These two effects are synergistic through a local feedforward loop, as there is an autocrine/paracrine secretion of Oxt by OB induced by estrogens [15]. Although Oxt stimulates OC differentiation, it also inhibits the activity of mature OCs, resulting in no effects on bone resorption because Oxt reduces osteoprotegerin expression and increases RANKL expression by OB promoting OC differentiation [15]. However, in an in vitro culture of OB where the precursors were treated with Oxt, the number of OCs was increased but their ability to resorb was diminished. The decreased resorbing capacity of OC induced by Oxt is explained by the ability of Oxt to increase intracellular calcium that increases NO production, diminishing OC activities [15]. Unexpectedly, Oxt/Oxtr knockout mice develop high bone mass secondary to obesity and low sympathetic tone [20][21].

3.2. Ex Vivo Studies

In ovariectomized (OVX) rats, intraperitoneal injection of Oxt prevents the decrease in the number of OBs and osteocytes, as well as in the osteoprotegerin/RANKL serum ratio, and the increase in bone turnover markers [15]. Oxt has a direct action on the skeleton that appears to be related to a peripheral action of Oxt and not to an indirect action through the CNS [20]. At the tissue level, the Oxt treatment improves the microarchitecture. The beneficial effects on bone density and microarchitecture of Oxt systemic administration have been confirmed by other studies in OVX rats and rabbits [22]. Indeed, the systemic administration of Oxt promotes peri-implant bone healing and osseointegration of titanium implants [23]. Marrow fat content increases with trabecular microarchitecture deterioration and is connected to the prevalence of bone fracture in osteoporosis [24][25]. In Ovx mice, a subcutaneous injection of Oxt reverses bone loss assessed using micro-computed tomography and reduces bone marrow adiposity by decreasing marrow adipocyte density [18]. Oxt serum levels were not correlated to any other measured neuro-pituitary hormone, including leptin and estradiol, and logistic regression analysis showed that osteoporosis status remained significantly correlated to Oxt serum levels regardless of age [15]. These data reinforce the fact that the anabolic effect of Oxt on bone is related to a direct and peripheral action on bone cells independently of estradiol–Oxt-mediated action [26][27]. In line with animal studies regarding the sex-specific action of Oxt in a large prospective cohort of men (MINOS), Oxt serum levels were not associated with BMD bone turnover rate or prevalent fractures [26][27], but serum Oxt level was significantly lower in men with severe osteoporosis compared to men with normal bone status suggesting the effects of Oxt on other determinants of fracture risk such as muscle strength [26][27]. As Oxt has pleiotropic effects, the therapeutic perspective is very promising. Indeed, Oxt has wide implications for general health; Oxt is a stress-coping molecule with anti-inflammatory and antioxidant properties, influences the immune system, body composition, cognitive functions, and mood, and has been tested in the treatment of numerous diseases including anxiety, pain, diabetes, cardiovascular diseases, and breast cancer [28][29][30]. Oxt requires a proper transport system to be delivered to the desired cells and tissues, thereby enabling the activation of the Oxtr in the target cells. In this regard, nanomedicine and the development of delivery systems represent a very active research area including the administration of nanoparticles carrying different compounds, including Oxt.

4. Year—2009: Oxytocin Is in Fat and Is Involved in the Onset of Metabolic Syndrome

More than 10 years ago, the laboratory raised the notion that the hormone/neurotransmitter Oxt is related to the regulation of energy and metabolism. It all started when researchers noticed that mice homozygous for deletions of Oxt/Oxtr develop late-onset obesity and metabolic syndrome. Oxt and Oxtr knockout mice develop high bone mass secondary to obesity and low sympathetic tone [20][21]. What sparked researchers' interest at that time was that Oxt- and Oxtr-deficient mice developed their metabolic phenotype in the absence of hyperphagia. This is in contrast to the expectation that hypothalamic Oxt decreases food intake by increasing leptin concentration in plasma [31][32][33]. Moreover, the metabolic role of Oxt is different in young versus older animals or it takes time to reach full force. This concept was named in researchers' laboratory “the oxytocin paradox”. Several explanations have been given to this discrepancy, including that Oxt may only mark the identity of neurons projecting from PVN, but its action is mediated by classical neurotransmitters such as GABA; alternatively, Oxt may be anorexigenic in normal mice, but developmental mechanisms may compensate for its absence in Oxt−/− or Oxtr−/− mice [32][34][35]. The appetite of Oxt−/− reported as normal, in spite of the hyperleptinemia, was possibly excessive relative to the level of adiposity [36]. This was not the case since the stomachs of Oxt-deficient mice were reported comparable to wildtype mice for size and weight, ruling out any excess in food consumption [32][37]. The tipping point of these observations was that Oxtr-deficient mice are thermogenically impaired, with a basal temperature lower than wildtype. This shed a light on the role of Oxt on temperature regulation and lean/fat mass composition of this model [31]. However, the lean/fat mass composition specific to skeletal muscle could be the reason for the normophagic obesity in this model. From this first point, it took researchers about 10 additional years of study to come to the conclusion that the effects of Oxt on metabolism and energy are both direct, as Oxt is anorexigenic, and indirect, as Oxt acts specifically on muscles potentiating the majority of the slow-twitch muscles, as well as the uterus [31][34]. The normophagic obesity of Oxt−/− mice was probably caused by a general muscular loss of function that slowly increased the intramuscular adipose tissue and ectopic fat accumulation in skeletal muscle and ultimately drove the late-onset obesity and metabolic phenotype rather than increased food consumption. The presence of concomitant sarcopenia and obesity confers worse functional outcome compared to either alone. Nevertheless, the study of Oxt in skeletal muscle and fat accumulation needs further investigation. Studies on genetic models of obesity have highlighted that nutritional status does not always determine Oxt concentrations in blood. For example, in ob/ob mice, which are homozygous for leptin expression, no difference in serum Oxt was detected relative to wildtype, whereas, in db/db mice, which are leptin-resistant because they lack the long isoform of the leptin receptor Ob-Rb, serum Oxt concentrations were decreased relative to lean control mice [9][38].

5. Year—2016: Oxytocin Regulates Thermogenesis and “The Oxytonic Effect”

5.1. Oxytocin in Muscle Adaptation after Cold Stress Challenge

Oxt regulates a diversity of social behaviors related to reproduction. Indeed, Oxt concentration increases during challenging situations including pregnancy and lactation, triggering aggressive behavior that is important after labor for the protection of the offspring when the offspring is most vulnerable to predators and Oxt concentration in plasma is at its peak [39]. Consistent with this knowledge, researchers hypothesized that Oxt may increase muscle tone to ensure a better response to the “fight response”. Hence, to trigger skeletal muscle contractions activated by Oxt, researchers elaborated a model of CS exposing mice to 4 °C for a shorter or longer time [40][41][42]. The thermogenic challenge increases Oxtr mRNA expression in Soleus muscle (Sol) and decreases circulating Oxt following a negative feedback loop in brain. The increase in Oxtr mRNA in skeletal muscle is phenotype-dependent, with Oxt potentiating the slow-twitch muscle phenotype through the regulation of myosin heavy chain 1 (slow oxidative)/myosin heavy chain 2b (fast glycolytic) ratio after CS, consistent with the shivering needs of thermogenesis. Oxt mRNA increases in bone after CS to balance the decreases in circulating Oxt. Researchers concluded that Oxt increases skeletal muscle tonicity in the same manner it does with the uterus, triggering what researchers called “the oxytonic contractions” after CS. Specifically, researchers explored the involvement of Oxtr/TRPV1 genes and Oxt on the adaptation of skeletal muscle to CS in mice. Oxt/Oxtr mRNA was measured in Sol and Tibialis anterioris (TA) by RT-PCR. Oxtr expression was analyzed in PVN and SON and hippocampus (HIPP) by immunohistochemistry, and circulating Oxt was measured in plasma. Potentiation of slow-twitch muscle after CS is observed in rat and mice [41][43]. Oxt may lead to the activation of transmembrane ion channels permeable to calcium ions such as the TRPV1 cation channel, which plays a key role as a thermal and analgesic effector in different tissues [44]. TRPV1 mediates the pain signaling of Oxt in neurons and Oxt may directly interact with TRPV1 as previously seen for Oxt analogues in invertebrates [45][46][47]. Oxt/Oxtrs are implicated in the regulation of energy homeostasis [31][32]. Oxt/Oxtr−/− mice show late-onset obesity but are normophagic, and this is probably caused by reduced metabolic rate and energy expenditure [31][32]. Oxtr−/− mice are thermogenically impaired and show decreased core body temperature after acute exposure to cold [31][48][49]. Skeletal muscle is also a source of heat in CS animals and humans through voluntary contractions from exercising muscle or involuntary as contractions from shivering muscle [50]. CS activates the involuntary activation of skeletal muscle movements [51]. Oxtr is present in human myoblasts [52][53]. Oxt was first described for its tonic smooth muscle regulation of gastric motility, showing that exogenous Oxt excited circular muscle strips and isolated smooth muscle of the gastric body and contracted the slow-twitch muscle of mammary gland and myometrium [54][55]. On the basis of this rationale in an interorgan approach to the physiology of CS, researchers formulated the hypothesis that Oxt may contract all the slow-twitch muscles as Oxt contracts the uterus, having a tonic, thermogenic, and analgesic effect [34], and that the metabolic syndrome of Oxt/Oxtr−/− mice was caused by muscular failure and depotentiation rather than increased food consumption. However, the main peripheral effects of Oxt are located in adipose tissue rather than skeletal muscle, as the expression levels in white adipose tissue (WAT) were comparable to classical Oxt target tissues [56]. Nevertheless, the expression level of Oxtr in skeletal muscle increases after thermogenic stress and is phenotype-dependent [34][57], as shown by the increase in myosin heavy chain 1 (slow-oxidative)/myosin heavy chain 2b (fast-glycolytic) (Mhc1/Mhc2b) gene expression ratio in Sol but not in TA muscle, together with the upregulation of the Oxtr gene in Sol muscle [40]. Brain Oxt may upregulate the short-term response of Sol, while it may downregulate the brain–Sol intercommunication after long-term exposure to CS, as shown by a linear correlation curve in a feedforward/feedback regulation between brain and Sol [40][41]. This means that low circulating Oxt levels are required for a better response to long-term CS challenge. Nevertheless, the Oxt signaling is maintained by the upregulation of Oxtr gene found in Sol muscle after long-term CS that balances the low level of circulating Oxt, consistent with previous studies [58]. In vivo data confirmed the in vitro data since Oxt expression in hypothalamus and Oxtr expression in adipose tissue were induced by CS, regulating both shivering and non-shivering thermogenesis [34]. Oxtr expression in PVN and Hipp increased after both long- and short-term CS exposure, as shown by immunohistochemistry, consistent with gene expression data in whole brain [9][42].

5.2. The Oxytonic Effect

The pathway described above was named in the researchers' laboratory “the oxytonic effect”. The actions of Oxt can be mediated by Oxtr that is a type A GPCR responsible for the release of calcium from the intracellular stores and activation of PKC. The TRPV1 cation channel is a thermal and analgesic effector in different tissues. TRPV1 mediates the pain signaling of Oxt in neurons. Circulating Oxt, in addition to Oxtrs, can directly interact with TRPV1 [44][47]. This is consistent with the hypothesis that Oxt has analgesic effects. CS induces the expression of TRPV1 and Oxtrs in skeletal muscle and is higher in slow-twitch skeletal muscle. Circulating Oxt leads to activation of Oxtrs and TRPV1 channels on the membrane. Oxtr and TRPV1 genes increased after 6 h and 5 days CS in Sol and TA. Regression analysis showed a significant linear correlation between Oxtr and TRPV1 in Sol and to a lesser extent in TA. The correlation between Oxtrs and TRPV1 in Sol and TA was lost at thermoneutrality, consistent with the coupling between these two genes at CS [34]. However, recent data have also shown that direct Oxtr stimulation inhibited lysosomal and proteolysis in rat oxidative skeletal muscle associated with Akt/FoxO1 pathway activation. Muscle incubation with an Oxtr-selective agonist did not alter protein synthesis, but in vivo short-term Oxt treatment intensified this process that resulted in Sol muscle mass gain, indicating that Oxt in vivo effects may be indirect through mediators not yet determined [59]. These in vivo Oxt effects in muscle anabolism could be mediated by the stimulation of the sympathetic autonomic nervous system, since there is evidence that Oxt stimulates secretion of adrenaline and sympathetic preganglionic neurons [60]. Oxt KO mice have less adrenaline release and develop sarcopenia [32][61].

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