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In situ expression of Ucn mRNA in different endocrine status in the PVN and DLS of the rat brain. Coronal tissue sections were processed for ISH using the U1 DIG-labeled probe. Values correspond to the mean SEM of three to seven independent experiments. Analysis by one-way ANOVA showed a significant difference between experimental conditions in both areas studied (PVN: F 14.17, R 2 0.76, p 0.0001; DLS: F 8.65, R 2 0.60, p 0.0002). Newman–Keuls multiple comparison post hoc test gave the following significances: PVN, F, p 0.05 compared with estrus, p 0.01 compared with diestrus I, and p 0.001 compared with male and OVX, , p 0.05 compared with diestrus I and estrus, f, p 0.05 compared with diestrus I and estrus; DLS, , p 0.001 compared with diestrus I, and OVX, F, p 0.01 compared with diestrus I, estrus, and OVX, and p 0.001 compared with male, , p 0.05 compared with diestrus I and p 0.01 compared with OVX.
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Urocortin (Ucn), a highly conserved metazoan gene, is related to stress and feeding, behaviors with significant gender differences. We investigated whether estrogens regulate the expression of the Ucn gene using transient transfection in PC12 cells with the human Ucn (hUcn) promoter coupled to luciferase and either alpha or beta estrogen receptors...
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Urocortins 2 (Ucn 2), one of the corticotropin releasing factor (CRF) peptide family, is thought to be an endogenous ligand for CRF type 2 receptor (CRF-R2). We previously demonstrated that Ucn 2 is expressed in the corticotrophs of rat pituitary, and the mRNA expression and secretion of Ucn 2 in corticotrophs of rat anterior pituitary are regulate...
Corticotropin-releasing factor (CRF) and the closely related family of neuropeptides urocortins (Ucns) are ancient paracrine-signaling peptides secreted in both the central and peripheral neural circuits. CRF and Ucns released from the CNS (central) regulate a plethora of physiological processes that include food intake, inflammation, and bowel mot...
To investigate the subacute effects of a sustained intravenous infusion of urocortin-I (Ucn-I) in experimental heart failure (HF).
In eight sheep with pacing-induced HF, a 4-day infusion of Ucn-I (0.3 microg/kg/h) induced prompt (30 min) and sustained (4-day) increases in cardiac output (CO, Day 4: 1.8+/-0.2 vs. 2.3+/-0.2 L/min, P<0.001) and stroke...
Endometriosis is considered as a benign aseptic inflammatory disease, characterised by the presence of ectopic endometrium-like tissue. Its symptoms (mostly pain and infertility) are reported as constant stressors. Corticotropin releasing hormone (CRH) and urocortin (UCN) are neuropeptides, strongly related to stress and inflammation. The effects o...
Urocortin is a novel corticotropin-releasing factor-like peptide, first isolated from the rat midbrain, which has anorexigenic properties, possibly associated with its involvement in the stress axis. Urocortin has been implicated in blood pressure regulation, ACTH release and feed intake, but its role as an integral component of the reproduction-nu...
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... Urocortin-immunoreactive neurons are present in the PVN (as well as in other hypothalamic and extrahypothalamic nuclei), and the largest population is confined within the parvocellular part of the nucleus, but some cells have been detected also in the magnocellular part (Kozicz et al., 1998). Expression of urocortin mRNA in PVN is regulated by estrogen; in fact it varies according to the different phases of the oestrus cycle, decreases in the ovariectomized female, and increases after acute administration of estradiol (Haeger et al., 2006), Finally, Urocortin inhibits feeding behavior . ...
... In situ hybridization analyses have detected colocalization of ERβ mRNA with OXT, AVP and CRH in the PVN (Hrabovszky et al., 1998;Laflamme et al., 1998;Shughrue et al., 2002;Somponpun and Sladek, 2003), a finding that has been confirmed by more recent RNAscope in situ hybridization studies (Kanaya et al., 2019). In addition, in situ hybridization has also been used to demonstrate coexpression of ERα with other molecules in the PVN, showing, for instance, the colocalization of urocortin and ERα mRNA in the rat PVN (Haeger et al., 2006). However, most of the analyses of colocalization of ERs with other factors in the PVN have been performed using immunohistochemical techniques. ...
... The distribution of ERβ immunoreactivity in the PVN is not restricted to OXT and AVP neurons and it has been also shown to be colocalized with CRH (Miller et al., 2004;Suzuki and Handa, 2005), nocipeptin/ orphanin FQ (Isgor et al., 2003b) and prolactin (Suzuki and Handa, 2005), expressed in a subpopulation of AVP neurons (Mejia et al., 1997), in the PVN of rats. Furthermore, ERα immunoreactivity has been shown to be colocalized with nNOS in the mouse PVN (Xue et al., 2009) and with urocortin in the PVN of rats (Haeger et al., 2006). ...
Estradiol and hypothalamic paraventricular nucleus (PVN) help coordinate reproduction with body physiology, growth and metabolism. PVN integrates hormonal and neural signals originating in the periphery, generating an output mediated both by its long-distance neuronal projections, and by a variety of neurohormones produced by its magnocellular and parvocellular neurosecretory cells. Here we review the cyto-and chemo-architecture, the connectivity and function of PVN and the sex-specific regulation exerted by estradiol on PVN neurons and on the expression of neurotransmitters, neuromodulators, neuropeptides and neurohormones in PVN. Classical and non-classical estrogen receptors (ERs) are expressed in neuronal afferents to PVN and in specific PVN interneurons, projecting neurons, neurosecretory neurons and glial cells that are involved in the input-output integration and coordination of neurohormonal signals. Indeed, PVN ERs are known to modulate body homeostatic processes such as autonomic functions, stress response, reproduction, and metabolic control. Finally, the functional implications of the estrogenic modulation of the PVN for body homeostasis are discussed.
... Non-isotopic in situ hybridization was performed as described previously [98]. At 40 days of age, six normal and six prenatally undernourished rats were perfused with physiological saline followed by 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4, and the brains were removed and maintained in 20% sucrose for 72 h. ...
Prenatally malnourished rats develop hypertension in adulthood, in part through increased α1-adrenoceptor-mediated outflow from the paraventricular nucleus (PVN) to the sympathetic system. We studied whether both α1-adrenoceptor-mediated noradrenergic excitatory pathways from the locus coeruleus (LC) to the PVN and their reciprocal excitatory CRFergic connections contribute to prenatal undernutrition-induced hypertension. For that purpose, we microinjected either α1-adrenoceptor or CRH receptor agonists and/or antagonists in the PVN or the LC, respectively. We also determined the α1-adrenoceptor density in whole hypothalamus and the expression levels of α1A-adrenoceptor mRNA in the PVN. The results showed that: (i) agonists microinjection increased systolic blood pressure and heart rate in normotensive eutrophic rats, but not in prenatally malnourished subjects; (ii) antagonists microinjection reduced hypertension and tachycardia in undernourished rats, but not in eutrophic controls; (iii) in undernourished animals, antagonist administration to one nuclei allowed the agonists recover full efficacy in the complementary nucleus, inducing hypertension and tachycardia; (iv) early undernutrition did not modify the number of α1-adrenoceptor binding sites in hypothalamus, but reduced the number of cells expressing α1A-adrenoceptor mRNA in the PVN. These results support the hypothesis that systolic pressure and heart rate are increased by tonic reciprocal paraventricular–coerulear excitatory interactions in prenatally undernourished young-adult rats.
... mRNA levels of UCN1 in the Edinger-Westphal nucleus of male mice are approximately 10 times higher than in the Edinger-Westphal nucleus of female mice in diestrus and 1.6 times higher than in female mice in proestrus. Estrogen decreases the transcriptional activity of the UCN1 promoter via ERβ [144]. UCN1 immunoreactivity was also increased in the mid-brain region of male rats exhibiting alcohol preference behavior compared with controls, whereas UCN1 expression did not differ between control and alcohol-consuming female rats [145]. ...
No organ in the body is impervious to the effects of stress, and a coordinated response from all organs is essential to deal with stressors. A dysregulated stress response that fails to bring systems back to homeostasis leads to compromised function and ultimately a diseased state. The components of the corticotropin-releasing factor (CRF) family, an ancient and evolutionarily conserved stress hormone-receptor system, helps both initiate stress responses and bring systems back to homeostasis once the stressors are removed. The mammalian CRF family comprises of four known agonists, CRF and urocortins (UCN1–3), and two known G protein-coupled receptors (GPCRs), CRF1 and CRF2. Evolutionarily, precursors of CRF- and urocortin-like peptides and their receptors were involved in osmoregulation/diuretic functions, in addition to nutrient sensing. Both CRF and UCN1 peptide hormones as well as their receptors appeared after a duplication event nearly 400 million years ago. All four agonists and both CRF receptors show sex-specific changes in expression and/or function, and single nucleotide polymorphisms are associated with a plethora of human diseases. CRF receptors harbor N-terminal cleavable peptide sequences, conferring biased ligand properties. CRF receptors have the ability to heteromerize with each other as well as with other GPCRs. Taken together, CRF receptors and their agonists due to their versatile functional adaptability mediate nuanced responses and are uniquely positioned to orchestrate sex-specific signaling and function in several tissues.
... We further investigated the effect of ER on CRH mRNA expression and the underlying mechanism (Chen et al., 2008). Although in PC12 cells estrogen receptors α and β were reported to differentially regulate the transcriptional activity of urocortin (UCN, another member of CRH family) via a half ERE and a CRE site, respectively (Haeger et al., 2006), we found in the BE2C cell line (a human neuroblastoma cell line which express endogenous CRH), both ERα and ERβ can significantly stimulate the CRH gene expression. ChIP assays further showed that both of the ER subtypes can be recruited by the CRH promoter in the presence of estradiol. ...
As a central player of the hypothalamic-pituitary-adrenal (HPA) axis, the corticotropin -releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) determine the state of HPA axis and play a key role in stress response. Evidence supports that during stress response the transcription and expression of CRH was finely tuned, which involved cis-element-transcriptional factor (TF) interactions and epigenetic mechanisms. Here we reviewed recent progress in CRH transcription regulation from DNA methylation to classic TFs regulation, in which a number of paired receptors were involved. The imbalance of multiple paired receptors in regulating the activity of CRH neurons indicates a possible molecular network mechanisms underlying depression etiology and directs novel therapeutic strategies of depression in the future.
... The estradiol E2 increases the activity of the promoter UCN via ER-, and decreases the activity of the human UCN promoter through ER-α. There is evidence that estrogens exert a direct transcriptional regulation and differential gene UCN [27] . The placenta, decidua and fetal membranes express mRNA UCN2-UCN3, localized in cytotrophoblast and syncytiotrophoblast cells, while only in the maternal and fetal vessels and amniotic cells can UCN2 be found. ...
The activities of corticotropin-releasing factor (CRF) and related peptides are mediated a number of receptors with seven transmembrane domains that are coupled to the Gs and Gq proteins. These receptors are known as CRF-Rs. In vitro studies have evidenced that urocortin (UCN) and CRF provoke an increase in the contractility of the uterus which is induced by endometrial prostaglandin F2a. Furthermore, through trophoblasts, it stimulates the secretion of adrenocorticotropic hormone (ACTH) and prostaglandin PGE2 and has a vasodilatory effect on the placenta. While it is well known that the placenta produces considerable quantities of CRF, several studies have, however, excluded that the placenta can generate significant quantities of UCN. In the short term, the human fetal adrenal gland produces more cortisol and dehydroepiandrosterone sulfate. The gestational tissues express UCN3 and UCN2 mRNA in cytotrophoblast and syncytiotrophoblast cells, while UCN2 is only to be found in the maternal and fetal vessels and amniotic cells. Nevertheless, gestational tissues express UCN2 and UCN3 differentially and do not stimulate placental ACTH secretion. In term pregnancies, maternal plasma levels of CRF and UCN are lower than at the beginning of pregnancy and are correlated to labor onset. Conversely, they do not decrease in post-term pregnancies. This evidence would seem to indicate that the fine-regulated expression of these neuropeptides is important in determining the duration of human gestation. In this scenario, low concentrations of UCN in the amniotic fluid at mid-term may be considered a sign of predisposition to preterm birth.
... Female mice were used because females are generally more sensitive to pain and to the effect of stress on pain (Fillingim et al., 2009) than males. Estrogen regulates promoter activity of the urocortin gene (Haeger et al., 2006), suggesting that some effects of urocortin may be more prominent in females. In addition, CRF lowers the firing rate of nociceptive-sensitive fibers in females and pre-adult males in locus ceruleus neurons (Borsody & Weiss, 1996). ...
Stress is antinociceptive in some models of pain but enhances musculoskeletal nociceptive responses in mice and muscle pain in patients with fibromyalgia syndrome. To test the hypothesis that urocortins are stress hormones that are sufficient to enhance tactile and musculoskeletal hyperalgesia, we measured von Frey fiber sensitivity and grip force after injection of corticotrophin releasing factor (CRF), urocortin I and urocortin II in mice. Urocortin I (a CRF1 and CRF2 receptor ligand) produced hyperalgesia in both assays when injected intrathecally (i.t.) but not intracerebroventricularly (i.c.v.), and only at a large dose when injected peripherally, suggesting a spinal action. Morphine inhibited urocortin I-induced changes in nociceptive responses in a dose-related fashion, confirming that changes in behavior reflect hyperalgesia rather than weakness. No tolerance developed to the effect of urocortin I (i.t.) when injected repeatedly, consistent with a potential to enhance pain chronically. Tactile hyperalgesia was inhibited by NBI-35965, a CRF1 receptor antagonist, but not astressin 2B, a CRF2 receptor antagonist. However, while urocortin I-induced decreases in grip force were not observed when coadministered i.t. with either NBI-35965 or astressin 2B, they were even more sensitive to inhibition by astressin, a nonselective CRF receptor antagonist. Together these data indicate that urocortin I acts at CRF receptors in the mouse spinal cord to elicit a reproducible and persistent tactile (von Frey) and musculoskeletal (grip force) hyperalgesia. Urocortin I-induced hyperalgesia may serve as a screen for drugs that alleviate painful conditions that are exacerbated by stress. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
... Lastly an interesting and extremely relevant finding is the relationship with Ucn1 and oestrogen. If oestrogen is responsible for the expression levels of Ucn1 in bone , [69] then the oestrogen/Ucn1 axis may be important in the development of postmenopausal osteoporosis. The relationship can be easily assessed using a Ucn1 KO animal model undergoing ovariectomy (OVX). ...
Bone is in a continual state of flux, with old bone being continually replaced by new. This bone turnover, or remodelling, needs to be highly regulated to prevent disorders associated with aberrant bone mass. This process is controlled principally by two cell types, osteoclasts and osteoblasts, which are responsible for bone resorption and deposition respectively. A crucial, well established regulatory mechanism involved in the control of these cells is the RANKL/RANK/ OPG pathway. With this, an osteoblast derived ligand, RANKL, binds to an osteoclastic receptor RANK, producing increased osteoclastogenesis and resorption. In contrast the Ucn system has only recently been found in bone cells, where an osteoblast and osteoclast derived ligand Ucn1, binds to an osteoclast derived receptor CRF-R2β, resulting in inhibition of osteoclastogenesis and resorption. Both systems possess a representative osteoblast derived binding factor with the potential to terminate the ligand signal. In this review we will briefly describe the discovery of the two systems and then go on to compare and contrast the respective components of these two bone regulatory mechanisms. We will review the pathways employed to produce their bone metabolising effects, and finally, we will speculate upon new areas of research which could be exploited to alleviate conditions associated with abnormal bone mass.
... The dorsomedial hypothalamus expresses both ERa and ERb and secretes both the orexigenic peptide, NPY, and the anorexigenic peptide CART. In the PVN, which responds to glucose and lipids, ERb is abundant and decreases the expression of urocortin, a potent anorexigenic peptide (Haeger et al. 2006). Stimulation of this nucleus increases food intake (Horvath 2006, Roepke 2009). ...
Estrogen and its receptors (ERs) influence many biological processes involved in physiology and pathology in men and women. ERs are involved in the etiology and/or progression of cancers of the prostate, breast, uterus, ovary, colon, lung, stomach, and malignancies of the immune system. In estrogen-sensitive malignancy, estrogen receptor β (ERβ) usually is a tumor suppressor and estrogen receptor α (ERα) an oncogene. ERβ regulates genes in several key pathways including tumor suppression (P53, PTEN); metabolism (PI3K); survival (AKT); proliferation (p45Skp2, cMyc and cyclin E); cell-cycle (p21WAF1, cyclin-dependent kinase inhibitor 1 (CDKN1A), p27Kip1 and cyclin-dependent kinase); protection from reactive oxygen species (glutathione peroxidase). ERs are also important in maintenance and function of healthy bone and brain in men and women. Because they are activated by small molecules ERs are excellent targets for pharmaceuticals. ERα antagonists have been used for many years in treatment of breast cancer and more recently pharmaceutical companies have produced agonists which are very selective for ERα or ERβ. ERβ agonists are being considered for preventing progression of cancer, treatment of anxiety and depression, as anti-inflammatory agents and as agents which prevent or reduce the severity of neurodegenerative diseases.
... Estrogens have been shown to modulate UCN expression in hypothalamus (Haeger et al., 2006). More recently, we have demonstrated that 17-b estradiol (E2) enhances UCN-induced vasodilation by maintenance of CRHR2 expression in arterial smooth muscle cells . ...
Estrogens have been suggested to exert cardioprotection through maintaining endogenous cardioprotective mechanisms. In present study, we investigated whether estrogens protect cardiomyocytes against hypoxia/reoxygenation (H/R) via modulating urocortins (UCNs) and their receptor corticotrophin-releasing hormone receptor type 2 (CRHR2). We found that 17β-estradiol (E2) enhanced UCN cardioprotection against H/R and increased CRHR2 expression in neonatal rat cardiomyocytes. E2 protected cardiomyocytes against H/R, which was impaired by CRHR2 antagonist or knockdown of CRHR2. Estrogen receptor α (ERα) antagonist treatment or ERα knockdown could abolish E2-induced CRHR2 up-regulation. Moreover, knockdown of Sp1 also attenuated E2-indueced CRHR2 up-regulation. Ovariectomy resulted in down-regulation of CRHR2 and Sp-1 in myocardium of mice, which was restored by E2 or ERα agonist treatment. These results suggest that estrogens act on ERα to up-regulate CRHR2 expression in cardiomyocytes, thereby enhancing cardioprotection of UCNs against H/R.
... In the cardiovascular system, for example, oestrogens inhibit cardiomyocyte apoptosis by decreasing reactive oxygen species production and increasing intracellular antioxidants [3]. Oestrogens may also indirectly control autophagy as they up-regulate urocortin [4], a neuropeptide hormone able to inhibiting autophagy in cardiomyocytes. Conversely, increasing evidence suggests possible adverse effects of androgens on the vasculature showing that androgens, as opposed to oestrogens, may worsen vascular dysfunction in men, thus contributing to sex-based differences in cardiovascular diseases [5]. ...
