School of BioSciences - Research Publications
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ItemShort-term (48hours) intravenous serelaxin infusion has no effect on myogenic tone or vascular remodeling in rat mesenteric arteries(WILEY, 2017-08)BACKGROUND: Short-term IV sRLX (recombinant human relaxin-2) infusion enhances endothelium-dependent relaxation in mesenteric arteries. This is initially underpinned by increased NO followed by a transition to prostacyclin. The effects of short-term IV sRLX treatment on pressure-induced myogenic tone and vascular remodeling in these arteries are unknown. Therefore, we investigated the effects of sRLX infusion on pressure-induced myogenic tone and passive mechanical wall properties in mesenteric arteries. METHODS: Mesenteric artery myogenic tone and passive mechanics were examined after 48-hours and 10-days infusion of sRLX. Potential mechanisms of action were assessed by pressure myography, qPCR, and Western blot analysis. RESULTS: Neither 48-hours nor 10-days sRLX treatment had significant effects on myogenic tone, passive arterial wall stiffness, volume compliance, or axial lengthening. However, in 48-hours sRLX -treated rats, incubation with the NO synthase blocker L-NAME significantly increased myogenic tone (P<.05 vs placebo), demonstrating an increased contribution of NO to the regulation of myogenic tone. eNOS dimerization, but not phosphorylation, was significantly upregulated in the arteries of sRLX -treated rats. CONCLUSION: In mesenteric arteries, 48-hours sRLX treatment upregulates the role of NO in the regulation of myogenic tone by enhancing eNOS dimerization, without altering overall myogenic tone or vascular remodeling.
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ItemDoes serelaxin treatment alter passive mechanical wall properties in small resistance arteries?(WILEY, 2016-11)The peptide hormone relaxin is recognized for its connective tissue remodeling actions in the reproductive tract during pregnancy and parturition, but it also has vascular remodeling actions independent of pregnancy. Recombinant human relaxin (serelaxin) treatment in male and non-pregnant female rodents enhances passive arterial compliance in the renal vasculature. This review focuses on serelaxin's actions on passive mechanical wall properties in small arteries and highlights the diversity of responses to serelaxin treatment in rodents. Different experimental approaches (duration of serelaxin treatment, rat strain, age) and animal models of disease (obesity, hypertension) will be considered. Most studies in young rodents demonstrate that serelaxin treatment fails to alter passive compliance in resistance-size arteries (mesenteric and femoral arteries and cerebral parenchymal arterioles), suggesting that serelaxin's beneficial effects are minimal in healthy animals. Short-term serelaxin treatment (5d) in aged, obese, and spontaneously hypertensive rats (SHRs) is largely without effect on passive mechanical wall properties. However, a longer duration of serelaxin treatment in SHRs (14d) enhances passive compliance in large muscular arteries as well as resistance-size arteries. In conclusion, serelaxin is capable of vascular remodeling. Its actions are vascular bed-dependent, more prominent in disease, and likely requires a longer duration of treatment to be effective.
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ItemVascular actions of relaxin: nitric oxide and beyond(WILEY, 2017-05)UNLABELLED: The peptide hormone relaxin regulates the essential maternal haemodynamic adaptations in early pregnancy through direct actions on the renal and systemic vasculature. These vascular actions of relaxin occur mainly through endothelium-derived NO-mediated vasodilator pathways and improvements in arterial compliance in small resistance-size arteries. This work catalysed a plethora of studies which revealed quite heterogeneous responses across the different regions of the vasculature, and also uncovered NO-independent mechanisms of relaxin action. In this review, we first describe the role of endogenous relaxin in maintaining normal vascular function, largely referring to work in pregnant and male relaxin-deficient animals. We then discuss the diversity of mechanisms mediating relaxin action in different vascular beds, including the involvement of prostanoids, VEGF, endothelium-derived hyperpolarisation and antioxidant activity in addition to the classic NO-mediated vasodilatory pathway. We conclude the review with current perspectives on the vascular remodelling capabilities of relaxin. LINKED ARTICLES: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.
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ItemTime-dependent activation of prostacyclin and nitric oxide pathways during continuous i.v. infusion of serelaxin (recombinant human H2 relaxin)(WILEY, 2016-03)BACKGROUND AND PURPOSE: In the RELAX-AHF trial, a 48 h i.v. serelaxin infusion reduced systemic vascular resistance in patients with acute heart failure. Consistent with preclinical studies, serelaxin augments endothelial vasodilator function in rat mesenteric arteries. Little is known about the contribution of endothelium-derived relaxing factors after a longer duration of continuous serelaxin treatment. Here we have assessed vascular reactivity and mechanistic pathways in mesenteric arteries and veins and the aorta after 48 or 72 h continuous i.v. infusion of serelaxin. EXPERIMENTAL APPROACH: Male rats were infused with either placebo or serelaxin (13.3 μg·kg(-1) ·h(-1) ) via the jugular vein using osmotic minipumps. Vascular function was assessed using wire myography. Changes in gene and protein expression and 6-keto PGF1α levels were determined by quantitative PCR, Western blot and ELISA respectively. KEY RESULTS: Continuous i.v. serelaxin infusion augmented endothelium-dependent relaxation in arteries (mesenteric and aorta) but not in mesenteric veins. In mesenteric arteries, 48 h i.v. serelaxin infusion increased basal NOS activity, associated with increased endothelial NOS (eNOS) expression. Interestingly, phosphorylated-eNOS(Ser1177) , eNOS and basal NOS activity were reduced in mesenteric arteries following 72 h serelaxin treatment. At 72 h, serelaxin treatment improved bradykinin-mediated relaxation through COX2-derived PGI2 production. CONCLUSIONS AND IMPLICATIONS: Continuous i.v. serelaxin infusion enhanced endothelial vasodilator function in arteries but not in veins. The underlying mediator at 48 h was NO but there was a transition to PGI2 by 72 h. Activation of the PGI2 -dependent pathway is key to the prolonged vascular response to serelaxin treatment.
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ItemTargeting the vascular dysfunction: Potential treatments for preeclampsia(WILEY, 2019-05)Preeclampsia is a pregnancy-specific disorder, primarily characterized by new-onset hypertension in combination with a variety of other maternal or fetal signs. The pathophysiological mechanisms underlying the disease are still not entirely clear. Systemic maternal vascular dysfunction underlies the clinical features of preeclampsia. It is a result of oxidative stress and the actions of excessive anti-angiogenic factors, such as soluble fms-like tyrosine kinase, soluble endoglin, and activin A, released by a dysfunctional placenta. The vascular dysfunction then leads to impaired regulation and secretion of relaxation factors and an increase in sensitivity/production of constrictors. This results in a more constricted vasculature rather than the relaxed vasodilated state associated with normal pregnancy. Currently, the only effective "treatment" for preeclampsia is delivery of the placenta and therefore the baby. Often, this means a preterm delivery to save the life of the mother, with all the attendant risks and burdens associated with fetal prematurity. To lessen this burden, there is a pressing need for more effective treatments that target the maternal vascular dysfunction that underlies the hypertension. This review details the vascular effects of key drugs undergoing clinical assessment as potential treatments for women with preeclampsia.
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ItemDifferential effects of relaxin deficiency on vascular aging in arteries of male mice(SPRINGER, 2015-08)Exogenous treatment with the naturally occurring peptide relaxin increases arterial compliance and reduces vascular stiffness. In contrast, relaxin deficiency reduces the passive compliance of small renal arteries through geometric and compositional vascular remodeling. The role of endogenous relaxin on passive mechanical wall properties in other vascular beds is unknown. Importantly, no studies have investigated the effects of aging in arteries of relaxin-deficient mice. Therefore, we tested the hypothesis that mesenteric and femoral arteries stiffen with aging, and this is exacerbated with relaxin deficiency. Male wild-type (Rln (+/+)) and relaxin knockout (Rln (-/-)) mice were aged to 3, 6, 12, 18, and 23 months. Passive mechanical wall properties were assessed by pressure myography. In both genotypes, there was a significant increase in circumferential stiffening in mesenteric arteries with aging, whereas in the femoral artery, aging reduced volume compliance. This was associated with a reduced ability of the artery to lengthen with aging. The predominant phenotype observed in Rln (-/-) mice was reduced volume compliance in young mice in both mesenteric and femoral arteries. In summary, aging induces circumferential stiffening in mesenteric arteries and axial stiffening in femoral arteries. Passive mechanical wall properties of Rln (-/-) mouse arteries predominantly differ at younger ages compared with Rln (+/+) mice, suggesting that a lack of endogenous relaxin only has a minor effect on vascular aging.
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ItemAnnexin-A1 deficiency exacerbates pathological remodelling of the mesenteric vasculature in insulin-resistant, but not insulin-deficient, mice(Wiley, 2020-04)Background and purpose Arterial stiffness, a characteristic feature of diabetes, increases the risk of cardiovascular complications. Potential mechanisms that promote arterial stiffness in diabetes include oxidative stress, glycation and inflammation. The anti‐inflammatory protein annexin‐A1 has cardioprotective properties, particularly in the context of ischaemia. However, the role of endogenous annexin‐A1 in the vasculature in both normal physiology and pathophysiology remains largely unknown. Hence, this study investigated the role of endogenous annexin‐A1 in diabetes‐induced remodelling of mouse mesenteric vasculature. Experimental approach Insulin‐resistance was induced in male mice (AnxA1+/+ and AnxA1‐/‐) with the combination of streptozotocin (55mg/kg i.p. x 3 days) with high fat diet (42% energy from fat) or citrate vehicle with normal chow diet (20‐weeks). Insulin‐deficiency was induced in a separate cohort of mice using a higher total streptozocin dose (55mg/kg i.p. x 5 days) on chow diet (16‐weeks). At study endpoint, mesenteric artery passive mechanics were assessed by pressure myography. Key results Insulin‐resistance induced significant outward remodelling but had no impact on passive stiffness. Interestingly, vascular stiffness was significantly increased in AnxA1‐/‐ mice when subjected to insulin‐resistance. In contrast, insulin‐deficiency induced outward remodelling and increased volume compliance in mesenteric arteries, regardless of genotype. In addition, the annexin‐A1 / formyl peptide receptor axis is upregulated in both insulin‐resistant and insulin‐deficient mice. Conclusion and implications Our study provided the first evidence that endogenous AnxA1 may play an important vasoprotective role in the context of insulin‐resistance. AnxA1‐based therapies may provide additional benefits over traditional anti‐inflammatory strategies for reducing vascular injury in diabetes.
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ItemAcute Intravenous Injection of Serelaxin (Recombinant Human Relaxin-2) Causes Rapid and Sustained Bradykinin-Mediated Vasorelaxation(WILEY, 2014-02)BACKGROUND: A recent clinical trial (RELAXin in Acute Heart Failure [RELAX-AHF]) demonstrated that 48 hours of continuous intravenous infusion of the vasorelaxant peptide serelaxin (recombinant human relaxin-2) to patients with acute heart failure reduced cardiovascular mortality at 180 days. The persistence of a vasorelaxant response as a potential mechanism for this long-term benefit and the vascular effects of a bolus intravenous injection of serelaxin have not been examined. This study investigates changes in resistance artery reactivity and passive mechanical wall properties following an intravenous serelaxin injection and whether these vascular effects persist in the absence of detectable circulating serelaxin. METHODS AND RESULTS: Male rats were injected with 13.3 μg/kg serelaxin into the tail vein; mesenteric arteries were assessed 3 and 24 hours after treatment by using wire-myography. Serelaxin increased basal nitric oxide synthase activity and reduced maximal contraction to endothelin-1 at 3 hours after administration. Serelaxin treatment also selectively enhanced bradykinin-mediated endothelium-dependent relaxation. This effect was sustained for 24 hours in the absence of circulating serelaxin. Serelaxin-mediated augmentation of bradykinin-evoked relaxation involved endothelium-derived hyperpolarization after 3 hours and prostacyclin-mediated relaxation after 24 hours. Furthermore, upregulation of inducible nitric oxide synthase, phosphorylation of protein kinase B at Ser473 and endothelial nitric oxide synthase at Ser1177 was observed at 24 hours after serelaxin injection. There were no effects of serelaxin on passive arterial wall stiffness. CONCLUSION: Our data show that a bolus intravenous injection of serelaxin modulates endothelial vasodilator function 3 hours after administration, an effect that was sustained for 24 hours. The prolonged bradykinin-mediated vasorelaxation is principally mediated through prostacyclin.
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ItemSerelaxin Elicits Bronchodilation and Enhances β-Adrenoceptor-Mediated Airway Relaxation(FRONTIERS MEDIA SA, 2016-10-27)Treatment with β-adrenoceptor agonists does not fully overcome the symptoms associated with severe asthma. Serelaxin elicits potent uterine and vascular relaxation via its cognate receptor, RXFP1, and nitric oxide (NO) signaling, and is being clinically evaluated for the treatment of acute heart failure. However, its direct bronchodilator efficacy has yet to be explored. Tracheal rings were prepared from male Sprague-Dawley rats (250-350 g) and tricolor guinea pigs, and precision cut lung slices (PCLSs) containing intrapulmonary airways were prepared from rats only. Recombinant human serelaxin (rhRLX) alone and in combination with rosiglitazone (PPARγ agonist; recently described as a novel dilator) or β-adrenoceptor agonists (isoprenaline, salbutamol) were added either to pre-contracted airways, or before contraction with methacholine or endothelin-1. Regulation of rhRLX responses by epithelial removal, indomethacin (cyclooxygenase inhibitor), L-NAME (nitric oxide synthase inhibitor), SQ22536 (adenylate cyclase inhibitor) and ODQ (guanylate cyclase inhibitor) were also evaluated. Immunohistochemistry was used to localize RXFP1 to airway epithelium and smooth muscle. rhRLX elicited relaxation in rat trachea and PCLS, more slowly than rosiglitazone or isoprenaline, but potentiated relaxation to both these dilators. It markedly increased β-adrenoceptor agonist potency in guinea pig trachea. rhRLX, rosiglitazone, and isoprenaline pretreatment also inhibited the development of rat tracheal contraction. Bronchoprotection by rhRLX increased with longer pre-incubation time, and was partially reduced by epithelial removal, indomethacin and/or L-NAME. SQ22536 and ODQ also partially inhibited rhRLX-mediated relaxation in both intact and epithelial-denuded trachea. RXFP1 expression in the airways was at higher levels in epithelium than smooth muscle. In summary, rhRLX elicits large and small airway relaxation via epithelial-dependent and -independent mechanisms, likely via RXFP1 activation and generation of NO, prostaglandins and cAMP/cGMP. rhRLX also enhanced responsiveness to other dilators, suggesting its potential as an alternative or add-on therapy for severe asthma.
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ItemRelaxin deficiency results in increased expression of angiogenesis- and remodelling-related genes in the uterus of early pregnant mice but does not affect endometrial angiogenesis prior to implantation(BIOMED CENTRAL LTD, 2016-03-22)BACKGROUND: Extensive uterine adaptations, including angiogenesis, occur prior to implantation in early pregnancy and are potentially regulated by the peptide hormone relaxin. This was investigated in two studies. First, we took a microarray approach using human endometrial stromal (HES) cells treated with relaxin in vitro to screen for target genes. Then we aimed to investigate whether or not relaxin deficiency in mice affected uterine expression of representative genes associated with angiogenesis and uterine remodeling, and also blood vessel proliferation in the pre-implantation mouse endometrium. METHODS: Normal HES cells were isolated and treated with recombinant human relaxin (10 ng/ml) for 24 h before microarray analysis. Reverse transcriptase PCR was used to analyze gene expression of relaxin and its receptor (Rxfp1) in ovaries and uteri; quantitative PCR was used to analyze steroid receptor, angiogenesis and extracellular matrix remodeling genes in the uteri of wild type (Rln+/+) and Rln-/- mice on days 1-4 of pregnancy. Immunohistochemistry localized endometrial endothelial cell proliferation and mass spectrometry measured steroid hormones in the plasma. RESULTS: Microarray analysis identified 63 well-characterized genes that were differentially regulated in HES cells after relaxin treatment. Expression of some of these genes was increased in the uterus of Rln+/+ mice by day 4 of pregnancy. There was significantly higher vascular endothelial growth factor A (VegfA), estrogen receptor 1 (Esr1), progesterone receptor (Pgr), Rxfp1, egl-9 family hypoxia-inducible factor 1 (Egln1), hypoxia inducible factor 1 alpha (Hif1α), matrix metalloproteinase 14 (Mmp14) and ankryn repeat domain 37 (Ankrd37) in Rln-/- compared to Rln+/+ mice on day 1. Progesterone receptor expression and plasma progesterone levels were higher in Rln-/- mice compared to Rln+/+ mice. However, endometrial angiogenesis was not advanced as pre-implantation endothelial cell proliferation did not differ between genotypes. CONCLUSIONS: Relaxin treatment modulates expression of a variety of angiogenesis-related genes in HES cells. However, despite accelerated uterine gene expression of steroid receptor, progesterone and angiogenesis and extracellular matrix remodeling genes in Rln-/- mice, there was no impact on angiogenesis. We conclude that although relaxin deficiency results in phenotypic changes in the pre-implantation uterus, endogenous relaxin does not play a major role in pre-implantation angiogenesis in the mouse uterus.