Effects Of Relaxin Research Articles

Relaxin decreases the severity of established hepatic fibrosis in mice.

Hepatic fibrosis is characterized by excess collagen deposition, decreased extracellular matrix degradation and activation of the hepatic stellate cells. The hormone relaxin has shown promise in the treatment of fibrosis in a number of tissues, but the effect of relaxin on established hepatic fibrosis is unknown. The aim of this study was to determine the effect of relaxin on an in vivo model after establishing hepatic fibrosis Male mice were made fibrotic by carbon tetrachloride treatment for 4 weeks, followed by treatment with two doses of relaxin (25 or 75 μg/kg/day) or vehicle for 4 weeks, with continued administration of carbon tetrachloride. Relaxin significantly decreased total hepatic collagen and smooth muscle actin content at both doses, and suppressed collagen I expression at the higher dose. Relaxin increased the expression of the matrix metalloproteinases MMP13 and MMP3, decreased the expression of MMP2 and tissue inhibitor of metalloproteinase 2 (TIMP2) and increased the overall level of collagen-degrading activity. Relaxin decreased TGFβ-induced Smad2 nuclear localization in mouse hepatic stellate cells. The results suggest that relaxin reduced collagen deposition and HSC activation in established hepatic fibrosis despite the presence of continued hepatic insult. This reduced fibrosis was associated with increased expression of the fibrillar collagen-degrading enzyme MMP13, decreased expression of TIMP2, and enhanced collagen-degrading activity, and impaired TGFβ signalling, consistent with relaxin's effects on activated fibroblastic cells. The results suggest that relaxin may be an effective treatment for the treatment of established hepatic fibrosis.

Treatment for cerebral small vessel disease: effect of relaxin on the function and structure of cerebral parenchymal arterioles during hypertension

We investigated the effect of hypertension on the function and structure of cerebral parenchymal arterioles (PAs), a major target of cerebral small vessel disease (SVD), and determined whether relaxin is a treatment for SVD during hypertension. PAs were isolated from 18-wk-old female normotensive Wistar-Kyoto (WKY) rats, spontaneous hypertensive rats (SHRs), and SHRs treated with human relaxin 2 for 14 d (4 μg/h; n=8/group) and studied using a pressurized arteriograph system. Hypertension reduced PA inner diameter (58±3 vs. 49±3 μm at 60 mmHg in WKY rats, P<0.05), suggesting inward remodeling that was reversed by relaxin (56±4 μm, P<0.05). Relaxin also increased PA distensibility in SHRs (34±2 vs. 10±2% in SHRs, P<0.05). Relaxin was detected in cerebrospinal fluid (110±30 pg/ml) after systemic administration, suggesting that it crosses the blood-brain barrier (BBB). Relaxin receptors (RXFP1/2) were not detected in cerebral vasculature, but relaxin increased vascular endothelial growth factor (VEGF) and matrix metalloproteinase 2 (MMP-2) expression in brain cortex. Inhibition of VEGF receptor tyrosine kinase (axitinib, 4 mg/kg/d, 14 d) had no effect on increased distensibility with relaxin, but caused outward hypertrophic remodeling of PAs from SHRs. These results suggest that relaxin crosses the BBB and activates MMP-2 in brain cortex, which may interact with PAs to increase distensibility. VEGF appears to be involved in remodeling of PAs, but not relaxin-induced increased distensibility.

Relaxin induces rapid, transient vasodilation in the microcirculation of hamster skeletal muscle

Relaxin produces a sustained decrease in total peripheral resistance, but the effects of relaxin on skeletal muscle arterioles, an important contributor to systemic resistance, are unknown. Using the intact, blood-perfused hamster cremaster muscle preparation in situ, we tested the effects of relaxin on skeletal muscle arteriolar microvasculature by applying 10(-10) M relaxin to second-, third- and fourth-order arterioles and capillaries. The mechanisms responsible for relaxin-induced dilations were explored by applying 10(-10) M relaxin to second-order arterioles in the presence of 10(-5) M N(G)-nitro-l-arginine methyl ester (l-NAME, nitric oxide (NO) synthase inhibitor), 10(-5) M glibenclamide (GLIB, ATP-dependent potassium (K(+)) channel inhibitor), 10(-3) M tetraethylammonium (TEA) or 10(-7) M iberiotoxin (IBTX, calcium-associated K(+) channel inhibitor). Relaxin caused second- (peak change in diameter: 8.3 ± 1.7 μm) and third (4.5 ± 1.1 μm)-order arterioles to vasodilate transiently while fourth-order arterioles did not (0.01 ± 0.04 μm). Relaxin-induced vasodilations were significantly inhibited by l-NAME, GLIB, TEA and IBTX. Relaxin stimulated capillaries to induce a vasodilation in upstream fourth-order arterioles (2.1 ± 0.3 μm), indicating that relaxin can induce conducted responses vasodilation that travels through blood vessel walls via gap junctions. We confirmed gap junction involvement by showing that gap junction uncouplers (18-β-glycyrrhetinic acid (40 × 10(-6) M) or 0.07% halothane) inhibited upstream vasodilations to localised relaxin stimulation of second-order arterioles. Therefore, relaxin produces transient NO- and K(+) channel-dependent vasodilations in skeletal muscle arterioles and stimulates capillaries to initiate conducted responses. The transient nature of the arteriolar dilation brings into question the role of skeletal muscle vascular beds in generating the sustained systemic haemodynamic effects induced by relaxin.

Treatment of cerebral small vessel disease with relaxin

Cerebral small vessel disease (SVD) associated with hypertension is a common cause of vascular cognitive impairment thought to be due to inward remodeling of brain parenchymal arterioles (PA) and white matter hypoperfusion. Here, we examined structural remodeling of PA in spontaneous hypertensive (SHR) and Wistar‐Kyoto rats (WKY; n=8/group) and if treatment with relaxin (4 μg/hr, osmotic pump for 2 wks), a peptide hormone shown to selectively enlarge PA, could reverse structural remodeling in SHR. PA were dissected from the brain parenchyma and studied pressurized in an arteriograph for passive structural measurements. PA from SHR had significantly smaller inner and outer diameters than WKY (49±3 vs. 58±3 μm and 62±3 vs. 71±3 μm at 60 mmHg; p&lt;0.01) that was reversed by relaxin treatment (56±4 and 67±4 μm; p&lt;0.01 vs. SHR). Relaxin treatment of SHR also increased PA distensibility (34±3 vs. 10±2 % in SHR at 60 mmHg; p&lt;0.01) without affecting blood pressure (MAP with and without relaxin in SHR: 140±5 vs.138±2 mmHg). In summary, chronic hypertension caused inward remodeling in PA that was reversed by relaxin treatment. The effect of relaxin on PA diameter and distensibility may improve perfusion to the white matter in chronic hypertension and thus may improve cerebral SVD. This study is supported by NIH NS045940 and HL095488.

Using the T2DN rat as a model to determine therapeutic efficacy of Serelaxin (recombinant human relaxin‐2) for Diabetic Nephropathy

Recent studies demonstrate renoprotective and antifibrotic effects of relaxin in non‐diabetic kidney disease. To test the hypothesis that relaxin protects against diabetic renal injury, we infused Serelaxin (RLX, 4ug/h, Corthera, s.c. minipump) or vehicle into 10–12 month old male T2DN rats for 3 weeks (n=10/group). An ELISA confirmed delivery of RLX (21±2 ng/mL plasma, nondetectable in control). Baseline protein excretion (142±27 vs 144±39 mg/d) and blood glucose (322±32 vs 296±31 mg/dL) were similar in RLX and untreated T2DN, respectively. After treatment, RLX and control groups showed no significant differences in blood glucose (313±18 vs 288±23 mg/dL), MAP (130±8 vs 118±7 mmHg), or proteinuria (212±48 vs 199±63 mg/d). Masson's trichrome staining of kidney sections revealed significant glomerular and tubulointerstitial injury in both groups, with no remarkable changes following RLX treatment. There were no differences between the RLX and control groups (n=5) in renal blood flow (6.0±1.7 vs 6.9±2.6 mL/min) or glomerular filtration rate (3.2±1.3 vs 3.3±1.2 mL/min). We conclude that the T2DN rat is a suitable model for diabetic nephropathy as it does exhibit progressive proteinuria and renal injury similar to human diabetic nephropathy; however, 3 weeks of RLX treatment is not sufficient to reverse established renal injury present in the T2DN rat. Earlier and/or longer treatment with RLX may be required.

Relaxin is a renal vasodilator in experimental models of cirrhosis and a potential novel therapy for hepatorenal syndrome in man

BackgroundHepatorenal syndrome is a feared complication of cirrhosis, with a high mortality rate and limited treatment options. The hallmarks of the disorder are functional renal failure, normal kidney histological findings, and profound renal vasoconstriction. The hormone relaxin mediates haemodynamic adaptations to pregnancy including increased renal blood flow and glomerular filtration rate (GFR). We hypothesised that relaxin could be used to modulate renal blood flow in cirrhosis. MethodsCirrhosis was induced in male rats by 16 weeks of carbon tetrachloride (intraperitoneally) and decompensated biliary cirrhosis by bile duct ligation. The effect of acute intravenous or extended (72 h) subcutaneous relaxin versus placebo was determined by analysis of systemic haemodynamics, renal blood flow, GFR, and organ histology. The effect of co-treatment with L-NG-nitroarginine methyl ester (L-NAME) was measured in subgroups of relaxin or placebo treated rats. Blood oxygen dependent-MRI (BOLD-MRI) was used to non-invasively detect changes to renal oxygenation. Hepatic and renal expression of RXFP1 (relaxin receptor) was determined by IHC and quantitative PCR (qPCR). A qPCR array was used to quantify changes in renal vasodilator/vasoconstrictor gene expression in response to relaxin. FindingsRXFP1 was detected in glomerular podocytes, renal pericytes, and renal, segmental, and interlobar arteries of cirrhotic rats. In carbon tetrachloride (CCl4) induced cirrhosis, acute intravenous relaxin (4 μg) induced a 50% increase in renal blood flow after 60 min (p<0·01 vs placebo, n=6). BOLD-MRI showed statistically significant (p<0·05) increased tissue oxygenation at the same timepoint in renal cortex and medulla. Extended subcutaneous relaxin increased renal blood flow by 54% in CCl4 (p<0·01 vs placebo, n=8) and 87% in bile duct ligated animals (p<0·05 vs placebo, n=3) and increased GFR by 138% in CCl 4 (p<0·01 vs placebo, n=8) and 70% in bile duct ligated animals (p<0·05 vs placebo, n=3). Mean arterial pressure was unaffected by relaxin. L-NAME (250 mg/L) orally abrogated the effect of relaxin on renal blood flow and GFR. Relative expression of vasoconstrictor genes in kidney was markedly reduced by relaxin treatment. InterpretationRelaxin increases renal blood flow in experimental models of cirrhosis. Crucially, relaxin also improves renal function and oxygenation and does not induce systemic hypotension even in advanced disease. These effects are modulated via augmentation of nitric oxide and downregulation of vasoconstrictors, pivotal in the pathogenesis of hepatorenal syndrome. Relaxin has potential as a novel therapy for hepatorenal syndrome, and further translational studies are warranted. FundingWellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative.

Relaxin antagonizes the effects of TGF-β/Smad3 axis on cardiac fibroblast-myofibroblast transition through the upregulation of Notch-1 signalling

The hormone relaxin (RLX) is produced by the heart and has beneficial actions on the cardiovascular system. We previously demonstrated that RLX stimulates mouse neonatal cardiomyocyte growth, suggesting its involvement in endogenous mechanisms of myocardial histogenesis and regeneration. In the present study, we extended the experimentation by evaluating the effects of RLX on primary cultures of neonatal cardiac stromal cells. RLX inhibited TGF-b1-induced fibroblast-myofibroblast transition, as judged by its ability to down-regulate a-smooth muscle actin and type I collagen expression. We also found that the hormone up-regulated metalloprotease (MMP)-2 and MMP-9 expression and downregulated the tissue inhibitor of metalloproteinases (TIMP)-2 in TGF-b1-stimulated cells. Interestingly, the effects of RLX on cardiac fibroblasts involved the activation of Notch-1 pathway. Indeed,Notch-1 expression was significantly decreased in TGF-b1-stimulated fibroblasts and this reduction was prevented by the addition of RLX to TGF-b1-stimulated cells. Moreover, pharmacological inhibition of endogenous Notch-1 signaling by DAPT, a g-secretase specific inhibitor, as well as the silencing of Notch-1 ligand, Jagged-1, potentiated TGF-b1-induced myofibroblast differentiation and abrogated the inhibitory effects of RLX. Interestingly, RLX and Notch-1 exerted their inhibitory effects by interfering with TGF-b1 signaling, since the addition of RLX to TGF-b1-stimulated cells caused a significant decrease in Smad3 phosphorylation, a typical downstream event of TGF-b1 receptor activation, while the treatment with a prevented this effect. These data suggest that Notch signaling can down-regulate TGF-b1/Smad3-induced fibroblast-myofibroblast transition and that RLX could exert its well known anti-fibrotic action through the up-regulation of this pathway. In conclusion, the results of the present study beside supporting the role of RLX in the field of cardiac fibrosis, provide novel experimental evidence on the molecular mechanisms underlying its effects.

Effects of relaxin in a co-culture of Sertoli and germ cells.

Spermatogenesis is controlled by FSH, testosterone and paracrine factors produced by Sertoli cells. The knockout of relaxin decreases sperm maturation in mice. Studies from our laboratory have shown that relaxin and its receptor RXFP1 are expressed in rat Sertoli cells, and exogenous relaxin stimulates Sertoli cell proliferation. Relaxin receptors are also detected in the rat germ cells at specific stages of development. Relaxin could therefore affect spermatogenesis either indirectly, by stimulating Sertoli cell proliferation, or directly, by affecting germ cells. The aim of the present study was to explore a role of relaxin at specific stages of spermatogenesis using a co-culture of rat Sertoli and germ cells. Relaxin seems to increase the number of pre-meiotic and meiotic cells.

Reproductive tract actions of relaxin in models of human pregnancy.

Elucidating the role(s) of relaxin in women has been greatly hampered by its species specificity. Suitable experimental models of relaxin action in women are limited. We established a non-human primate model of early human pregnancy to study the effects of relaxin in vivo and used three well characterized in vitro models of human endometrial function for study of mechanisms involved. Results from these studies clearly demonstrate that relaxin is an import ant factor in human endometrium which causes accommodation to and maintenance of early pregnancy and uses multiple physiological and biochemical mediators.

Muscular effects of relaxin on the mouse colon: mechanical and electrophysiological studies.

Relaxin has been reported to influence gastrointestinal motility in mice. However, at present, nothing is known about the effects of relaxin on the electrophysiological properties of the gastrointestinal smooth muscle. In the present experiments relaxin, other than influencing the colonic motility pattern, has been shown to act on cell membrane properties. The results of the present study indicate that relaxin directly modulates the motility of the proximal colon and the membrane potential of smooth muscle.

Relaxin, cardiac stem cells and heart regeneration.

The notion that the adult heart of mammals including humans contain a small population of resident cardiac progenitor/stem cells (CSCs) have questioned the traditional paradigm of the myocardium as a post-mitotic terminally differentiated tissue. These cells, however, are relatively scarce and unable to be recruited in large number at the site of tissue damage. This has sparkled novel interest in the identification of molecules capable of stimulating the regenerative potentials of CSCs in their microenvironment. In this context, the peptide hormone relaxin (RLX), recently validated as a cardiovascular hormone, deserves a key place. This article summarizes the most recent findings of our group on the ability of RLX to modulate growth and differentiation of mouse neonatal cardiomyocytes, suggesting that this hormone, for which the heart is both a source and target organ, may participate in the endogenous mechanisms of myocardial repair/regeneration. Moreover, we have recently observed that RLX, by a Notch-1-mediated mechanism, inhibits cardiac myofibroblast differentiation and function, suggesting that the known anti-fibrotic effects of RLX may be part of a complex network of actions whereby this hormone facilitates cardiac stem cell growth and improves myocardial regeneration.

Effects of H2 relaxin on the expression of Epac in a murine model of chronic asthma

To explore the effects of H(2) relaxin on the expression of exchange protein directly activated by cyclic adenosine monophosphate (Epac) in a murine model of chronic asthma and the roles in the management of airway remodelling. Thirty-two BALB/c mice were randomly divided into 4 groups of normal control, asthma, vehicle control and relaxin treatment (n = 8 each). They were sensitized and challenged with ovalbumin to establish a chronic asthmatic model. The vehicle control and relaxin treatment groups were subcutaneously injected with saline and relaxin (0.25 mg×kg(-1)×d(-1)) respectively. Alteration of airway inflammation was observed by hematoxylin-eosin (HE) staining. The airway expressions of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) were evaluated by immunohistochemistry. The protein expression of Epac and phosphorylated extracellular signal regulated kinases1/2 (p-ERK1/2) were detected by Western blot. Compared to those in the normal control group, massive infiltration of inflammatory cells, airway stenosis, bronchial smooth muscle hypertrophy were present in the asthmatic and vehicle control groups. The above-mentioned changes were significantly ameliorated in the relaxin treatment group. The percentage of PCNA positive cells (34.8% ± 6.1%, 33.5% ± 6.6%) and the expression of α-SMA ((1.70 ± 0.25), (1.54 ± 0.24) µm(2)/µm) in the asthmatic and vehicle control groups were significantly higher than those in the normal control group (9.9% ± 2.6%, (0.51 ± 0.16) µm(2)/µm) (all P < 0.05) while administration of relaxin decreased the airway expression levels of PCNA and α-SMA (22.9% ± 5.2%, (1.06 ± 0.25) µm(2)/µm) (all P < 0.05). The results of Western blot showed that the expression levels of Epac in the asthmatic and vehicle groups (0.62 ± 0.12, 0.68 ± 0.11) were lower than those in the control group (1.50 ± 0.17) (all P < 0.05) while it significantly increased in the relaxin group (1.08 ± 0.15) (all P < 0.05). The levels of phosphorylation of ERK1/2 in the asthmatic and vehicle groups (1.45 ± 0.13, 1.36 ± 0.09) were higher than those in the control group (0.38 ± 0.17) (all P < 0.05) while it decreased in the relaxin treatment group (0.72 ± 0.06) (all P < 0.05). No differences existed in all parameters between the asthmatic and vehicle groups (P > 0.05). Relaxin alleviates the airway inflammation and airway smooth muscle cell proliferation in a murine model of chronic asthma probably through activating Epac and inhibiting the phosphorylation of ERK1/2.

Identification of Key Residues Essential for the Structural Fold and Receptor Selectivity within the A-chain of Human Gene-2 (H2) Relaxin

Human gene-2 (H2) relaxin is currently in Phase III clinical trials for the treatment of acute heart failure. It is a 53-amino acid insulin-like peptide comprising two chains and three disulfide bonds. It interacts with two of the relaxin family peptide (RXFP) receptors. Although its cognate receptor is RXFP1, it is also able to cross-react with RXFP2, the native receptor for a related peptide, insulin-like peptide 3. In order to understand the basis of this cross-reactivity, it is important to elucidate both binding and activation mechanisms of this peptide. The primary binding mechanism of this hormone has been extensively studied and well defined. H2 relaxin binds to the leucine-rich repeats of RXFP1 and RXFP2 using B-chain-specific residues. However, little is known about the secondary interaction that involves the A-chain of H2 relaxin and transmembrane exoloops of the receptors. We demonstrate here through extensive mutation of the A-chain that the secondary interaction between H2 relaxin and RXFP1 is not driven by any single amino acid, although residues Tyr-3, Leu-20, and Phe-23 appear to contribute. Interestingly, these same three residues are important drivers of the affinity and activity of H2 relaxin for RXFP2 with additional minor contributions from Lys-9, His-12, Lys-17, Arg-18, and Arg-22. Our results provide new insights into the mechanism of secondary activation interaction of RXFP1 and RXFP2 by H2 relaxin, leading to a potent and RXFP1-selective analog, H2:A(4-24)(F23A), which was tested in vitro and in vivo and found to significantly inhibit collagen deposition similar to native H2 relaxin.

Relaxin exerts two opposite effects on mechanical activity and nitric oxide synthase expression in the mouse colon

The hormone relaxin exerts a variety of functions on the smooth muscle of reproductive and nonreproductive organs, most of which occur through a nitric oxide (NO)-mediated mechanism. In the stomach and ileum, relaxin causes muscle relaxation by modulating the activity and expression of different nitric oxide synthase (NOS) isoforms region-dependently. Nothing is known on the effects of relaxin in the colon, the gut region expressing the highest number of neuronal (n) NOSβ-immunoreactive neurons and mainly involved in motor symptoms of pregnancy and menstrual cycle. Therefore, we studied the effects of relaxin exposure in the mouse proximal colon in vitro evaluating muscle mechanical activity and NOS isoform expression. The functional experiments showed that relaxin decreases muscle tone and increases amplitude of spontaneous contractions; the immunohistochemical results showed that relaxin increases nNOSβ and endothelial (e) NOS expression in the neurons and decreases nNOSα and eNOS expression in the smooth muscle cells (SMC). We hypothesized that, in the colon, relaxin primarily increases the activity and expression of nNOSβ and eNOS in the neurons, causing a reduction of the muscle tone. The downregulation of nNOSα and eNOS expression in the SMC associated with increased muscle contractility could be the consequence of continuous exposue of these cells to the NO of neuronal origin. These findings may help to better understand the physiology of NO in the gastrointestinal tract and the role that the "relaxin-NO" system plays in motor disorders such as functional bowel disease.

Human relaxin-2: historical perspectives and role in cancer biology

One of the most recognised and studied family of peptide hormones is the insulin superfamily. Within this family is the relaxin subfamily which comprises seven members: relaxin-1, -2 and -3 and insulin-like peptides 3, 4, 5 and 6. Besides exhibiting sequence similarities, each member exists as an active A-B heterodimer linked by three disulfide bonds. This mini-review is divided into three broad themes: an overview of all insulin superfamily members (including structural similarities); roles of each superfamily member and finally, a focus on the pleiotropic peptide hormone, human relaxin-2. In addition to promoting vasodilatory effects leading to evaluation in Phase III clinical trials for the treatment of acute heart failure, relaxin has recently been shown to be highly expressed by cancer cells, aiding in their proliferation, invasiveness and metastasis. These contrary effects of relaxin are discussed together with current efforts in the development of relaxin antagonists that may possess future therapeutic potential for the treatment of certain cancers.

Intracellular signaling pathways involved in the relaxin-induced proliferation of rat Sertoli cells

Regulation of Sertoli cell number is a key event to determine normal spermatogenesis. We have previously shown that relaxin and its G-protein coupled receptor RXFP1 are expressed in rat Sertoli cells, and that relaxin stimulates Sertoli cell proliferation. This study examined the mechanisms underlying the mitogenic effect of relaxin in a primary culture of Sertoli cells removed from testes of immature rats. Stimulation with exogenous relaxin increased Sertoli cell number and the expression of the proliferating cell nuclear antigen (PCNA), but did not affect the mRNA level of the differentiation markers cadherins 1 and 2. Relaxin-induced Sertoli cell proliferation was blocked by inhibition of MEK/ERK1/2 or PI3K/AKT pathways, but not by inhibition of PKC or EGFR activity. Relaxin induced a rapid and transient activation of ERK1/2 phosphorylation, which was MEK and SRC-dependent, and involved upstream activation of Gi. AKT activation could be detected 5min after relaxin stimulation, and was still detected after 24h of stimulation with relaxin. Relaxin-induced AKT phosphorylation was Gi- but not PKA-dependent, and it was blocked by both PI3K and MEK inhibitors. In conclusion, the mitogenic effect of relaxin in Sertoli cell involves coupling to Gi and activation of both MEK/ERK1/2 and PI3K/AKT pathways.

Relaxin, Insulin and Diabetes: An Intriguing Connection

Until recently, relaxin and insulin were grouped into the same hormone superfamily because of substantial biochemical homologies. This notion has then changed with the understanding that insulin and relaxin are ligands for different receptors and signal transduction systems, namely, tyrosine kinase and G-protein-coupled receptors respectively. As a matter of fact, relaxin does not mimic the metabolic effects of insulin. The biological effects of insulin are much more clearly delineated than those of relaxin, which is traditionally viewed as a reproductive hormone involved in the maternal adjustments of pregnancy. In the last decade, evidence has been accumulating that relaxin has major effects on the heart, blood vessels and the extracellular matrix within connective tissues. In particular, pertaining to the relationships between relaxin and diabetes, relaxin was shown to promote arterial and microvascular dilation, thereby increasing organ perfusion, counteract ischemic injury, improve adverse cardiac and vascular remodeling, and promote extracellular matrix turn-over, thereby exerting anti-fibrotic effects. Thus, relaxin could blunt or delay the vascular and organ complication of diabetes. Whether relaxin may also synergize with insulin to optimize blood glucose homeostasis remains an unconfirmed issue. However, there are clues in the literature which, if gathered, speak in favor of this perspective. Moreover, preliminary data suggest that exogenous relaxin administration may improve insulin sensitivity in diabetic patients. Considering that human recombinant relaxin is under study as a novel, promising drug for the treatment of heart failure, a broader knowledge of the possible beneficial effects of relaxin in diabetes and its complications can be of interest to the scientific community.

Ex vivo pharmacology of surgical samples of the uterosacral ligament. Part II: Effects of oxytocin and relaxin on arteries and vascular plexus

The uterosacral ligament (USL) contains prominent vessels, the function of which is unknown. Here we study the relationship between smooth muscle of the USL and the vascular bundles. Native samples of arteries and vascular bundles were mounted in a perfusion chamber under the stereomicroscope. The effects of noradrenalin, carbachol, oxytocin, and relaxin were monitored by digital time-lapse video and quantified by image processing. Arteries were adrenergic and the smooth muscle in the adventitia cholinergic. Relaxin-2 shifted the dose response curve of noradrenalin to the right and widened the arterial lumen within 30 min. Oxytocin induced contraction of the adventitial smooth muscle leading to a slow opening of the artery. In a vascular bundle the differential pattern of both reactivities was demonstrated. In the USL the smooth muscle extends into the adventitial layer of blood vessels and forms a functional unit with the vascular plexus, which is regulated by relaxin and oxytocin.

PMO-129 Relaxin reduces portal hypertension through stimulation of hepatic nitric oxide production

IntroductionWe have previously reported that the multifunctional hormone relaxin (RLX) downregulated the activation state and contractility of hepatic myofibroblasts and reduced portal hypertension (PHT) in cirrhotic rats (Fallowfield J et...

Effect of Relaxin on Human Sperm Functions

Relaxin is a circulating hormone with functions in pregnancy, parturition, and other aspects of female reproduction. It is also secreted from the prostate gland into the seminal fluid; however, the role of relaxin in male reproduction is debated. Studies conducted in the past have suggested possible actions on human spermatozoa, but the data were contrasting. Here, we show that the relaxin receptor RXFP1 (Relaxin Family Peptide Receptor 1) is expressed in human spermatozoa, and it mainly localizes in the astrodome. In vitro studies on human sperm demonstrated that this hormone attenuates the natural decline in sperm motility and maintains higher mitochondrial activity and lower apoptosis level. Furthermore, relaxin induced an increase in sperm hyperactivation, intracellular calcium and cAMP, and acrosome reaction. These effects were abolished by the use of the specific anti-RXFP1 antibody. Relaxin concentrations were low in the blood (x ± SD, 0.16 ± 0.03 nM) and very high in the seminal plasma (x ± SD, 10.3 ± 4.0 nM), confirming its secretion mainly by the prostate. Taken together, these data demonstrate that relaxin influences positively many sperm functions linked to fertilizing ability, and it preserves sperm functionality, with possible practical value in assisted reproduction techniques.