{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:14:22Z","timestamp":1790802862804,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T00:00:00Z","timestamp":1607299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>\u03b23-adrenoreceptor (\u03b23-AR), a G-protein coupled receptor, has peculiar regulatory properties in response to oxygen and widespread localization. \u03b23-AR is expressed in the most frequent neoplasms, also occurring in pregnant women, and its blockade reduces tumor growth, indicating \u03b23-AR-blockers as a promising alternative to antineoplastic drugs during pregnancy. However, \u03b23-AR involvement in prenatal morphogenesis and the consequences of its blockade for the fetus remain unknown. In this study, after the demonstrated expression of \u03b23-AR in endothelial and smooth muscle cells of ductus arteriosus (DA), C57BL\/6 pregnant mice were acutely treated at 18.5 of gestational day (GD) with indomethacin or with the selective \u03b23-AR antagonist SR59230A, or chronically exposed to SR59230A from 15.5 to 18.5 GD. Six hours after the last treatment, fetuses were collected. Furthermore, newborn mice were treated straight after birth with BRL37344, a \u03b23-AR agonist, and sacrificed after 7 h. SR59230A, at the doses demonstrated effective in reducing cancer progression (10 and 20 mg\/kg) in acute and chronic mode, did not induce fetal DA constriction and did not impair the DA ability to close after birth, whereas at the highest dose (40 mg\/kg), it was shown to cause DA constriction and preterm-delivery. BRL37344 administered immediately after birth did not alter the physiological DA closure.<\/jats:p>","DOI":"10.3390\/cells9122625","type":"journal-article","created":{"date-parts":[[2020,12,7]],"date-time":"2020-12-07T21:37:42Z","timestamp":1607377062000},"page":"2625","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Effect of Beta 3 Adrenoreceptor Modulation on Patency of the Ductus Arteriosus"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9828-2082","authenticated-orcid":false,"given":"Alessandro","family":"Pini","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Fazi","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2374-5147","authenticated-orcid":false,"given":"Patrizia","family":"Nardini","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0750-4706","authenticated-orcid":false,"given":"Maura","family":"Calvani","sequence":"additional","affiliation":[{"name":"Department of Paediatric Haematology-Oncology, A. Meyer University Children\u2019s Hospital, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3383-3896","authenticated-orcid":false,"given":"Sergio","family":"Fabbri","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health, Section of Pharmacology and Toxicology, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8224-4919","authenticated-orcid":false,"given":"Alessandro","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medical Sciences, University of Bologna, 40064 Ozzano dell\u2019Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Forni","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health, Section of Pediatric Neurosciences, \u201cA. Meyer\u201d University Children\u2019s Hospital, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"La Marca","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Psychology, Drug Research and Child Health, Section of Pediatric Neurosciences, \u201cA. Meyer\u201d University Children\u2019s Hospital, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6139-9241","authenticated-orcid":false,"given":"Arianna Carolina","family":"Rosa","sequence":"additional","affiliation":[{"name":"Department of Scienza e Tecnologia del Farmaco, University of Turin, 10125 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5310-9147","authenticated-orcid":false,"given":"Luca","family":"Filippi","sequence":"additional","affiliation":[{"name":"Division of Neonatology and NICU, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1126\/science.2570461","article-title":"Molecular characterization of the human beta 3-adrenergic receptor","volume":"245","author":"Emorine","year":"1989","journal-title":"Science"},{"key":"ref_2","first-page":"548","article-title":"The human beta 3-adrenergic receptor is resistant to short term agonist-promoted desensitization","volume":"43","author":"Nantel","year":"1993","journal-title":"Mol. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s00210-012-0828-x","article-title":"Beta3-adrenergic receptors modulate vascular endothelial growth factor release in response to hypoxia through the nitric oxide pathway in mouse retinal explants","volume":"386","author":"Filippi","year":"2013","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1038\/sj.bjp.0703491","article-title":"Functional, biochemical and molecular biological evidence for a possible beta(3)-adrenoceptor in human near-term myometrium","volume":"130","author":"Bardou","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_5","first-page":"11","article-title":"Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes\u2014an update","volume":"25","author":"Weyer","year":"1999","journal-title":"Diabetes Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17686","DOI":"10.1074\/jbc.272.28.17686","article-title":"Beta3-adrenergic receptors on white and brown adipocytes mediate beta3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice","volume":"272","author":"Grujic","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.phrs.2009.01.002","article-title":"The beta3-adrenoceptor as a therapeutic target: Current perspectives","volume":"59","author":"Ursino","year":"2009","journal-title":"Pharmacol. Res."},{"key":"ref_8","first-page":"169","article-title":"Beta 3 adrenergic receptors: Molecular, histological, functional and pharmacological approaches","volume":"50","author":"Coman","year":"2009","journal-title":"Romanian J. Morphol. Embryol. Rev. Roum. Morphol. Embryol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Schena, G., and Caplan, M.J. (2019). Everything You Always Wanted to Know about \u03b2(3)-AR * (* But Were Afraid to Ask). Cells, 8.","DOI":"10.3390\/cells8040357"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1007\/s11897-011-0064-6","article-title":"Beta-3 adrenoceptors as new therapeutic targets for cardiovascular pathologies","volume":"8","author":"Gauthier","year":"2011","journal-title":"Curr. Heart Fail. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/j.1476-5381.1994.tb17049.x","article-title":"Atypical beta-adrenoceptors in the rat isolated common carotid artery","volume":"113","author":"Oriowo","year":"1994","journal-title":"Br. J. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"PL269","DOI":"10.1016\/0024-3205(95)00076-3","article-title":"Different atypical beta-adrenoceptors mediate isoprenaline-induced relaxation in vascular and non-vascular smooth muscles","volume":"56","author":"Oriowo","year":"1995","journal-title":"Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s00210-010-0526-5","article-title":"Pharmacological evidence for the presence of functional beta(3)-adrenoceptors in rat retinal blood vessels","volume":"382","author":"Mori","year":"2010","journal-title":"Naunyn. Schmiedebergs Arch. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.tips.2011.02.008","article-title":"Previously unsuspected widespread cellular and tissue distribution of beta-adrenoceptors and its relevance to drug action","volume":"32","author":"Daly","year":"2011","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1007\/s00109-013-1073-6","article-title":"Functional involvement of beta3-adrenergic receptors in melanoma growth and vascularization","volume":"91","author":"Casini","year":"2013","journal-title":"J. Mol. Med. Berl."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Calvani, M., Bruno, G., and Dal Monte, M. (2019). beta3 -Adrenoceptor as a potential immuno-suppressor agent in melanoma. Int. J. Mol. Sci., 176.","DOI":"10.1111\/bph.14660"},{"key":"ref_17","first-page":"6816508","article-title":"beta3-Adrenoreceptors Control Mitochondrial Dormancy in Melanoma and Embryonic Stem Cells","volume":"2018","author":"Calvani","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/s41388-019-0993-1","article-title":"\u03b23-adrenoreceptor blockade reduces tumor growth and increases neuronal differentiation in neuroblastoma via SK2\/S1P(2) modulation","volume":"39","author":"Bruno","year":"2020","journal-title":"Oncogene"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.bbi.2012.01.013","article-title":"Chronic stress enhances progression of acute lymphoblastic leukemia via beta-adrenergic signaling","volume":"26","author":"Lamkin","year":"2012","journal-title":"Brain. Behav. Immun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1159\/000163851","article-title":"Upregulation of beta3-adrenergic receptor mRNA in human colon cancer: A preliminary study","volume":"75","author":"Perrone","year":"2008","journal-title":"Oncology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6446","DOI":"10.18632\/oncotarget.14119","article-title":"Use of non-selective beta-blockers is associated with decreased tumor proliferative indices in early stage breast cancer","volume":"8","author":"Montoya","year":"2017","journal-title":"Oncotarget"},{"key":"ref_22","first-page":"S348","article-title":"Cancer and pregnancy: What should we know about the management with systemic treatment of pregnant women with cancer?","volume":"47","author":"Pavlidis","year":"2011","journal-title":"Eur. J. Cancer Oxf. Engl. 1990"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1634\/theoncologist.2015-0362","article-title":"The Treatment of Colorectal Cancer During Pregnancy: Cytotoxic Chemotherapy and Targeted Therapy Challenges","volume":"21","author":"Rogers","year":"2016","journal-title":"Oncologist"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1067\/mob.2002.125277","article-title":"Beta2- and beta3-adrenoreceptor agonists: Human myometrial selectivity and effects on umbilical artery tone","volume":"187","author":"Dennedy","year":"2002","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"R1312","DOI":"10.1152\/ajpregu.00004.2008","article-title":"Long-term hypoxia modulates expression of key genes regulating adipose function in the late-gestation ovine fetus","volume":"294","author":"Myers","year":"2008","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1113\/jphysiol.1963.sp007249","article-title":"The response of the isolated ductus arteriosus to oxygen and anoxia","volume":"169","author":"Kovalcik","year":"1963","journal-title":"J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1152\/physrev.1975.55.1.62","article-title":"Control of the ductus arteriosus","volume":"55","author":"Heymann","year":"1975","journal-title":"Physiol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1139\/y73-031","article-title":"The response of the ductus arteriosus to prostaglandins","volume":"51","author":"Coceani","year":"1973","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.acvd.2010.06.006","article-title":"The ductus arteriosus: Physiology, regulation, and functional and congenital anomalies","volume":"104","author":"Gournay","year":"2011","journal-title":"Arch. Cardiovasc. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0262-1746(87)90074-6","article-title":"Effect of dexamethasone on fetal lung 15-hydroxy-prostaglandin dehydrogenase: Possible mechanism for the prevention of patent ductus arteriosus by maternal dexamethasone therapy","volume":"27","author":"Tsai","year":"1987","journal-title":"Prostaglandins. Leukot. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/pr.2014.108","article-title":"Pharmacokinetics and local safety profile of propranolol eye drops in rabbits","volume":"76","author":"Padrini","year":"2014","journal-title":"Pediatr. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"R1717","DOI":"10.1152\/ajpregu.00259.2006","article-title":"Inhibition of cyclooxygenase isoforms in late- but not midgestation decreases contractility of the ductus arteriosus and prevents postnatal closure in mice","volume":"291","author":"Reese","year":"2006","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_33","first-page":"354","article-title":"Increased constriction of the ductus arteriosus by dexamethasone, indomethacin, and rofecoxib in fetal rats","volume":"69","author":"Takami","year":"2005","journal-title":"Circ. J. Off. J. Jpn. Circ. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/S0304-3940(97)00511-9","article-title":"Gene expression of catecholamine synthesizing enzymes and beta adrenoceptor subtypes during rat embryogenesis","volume":"231","author":"Fujinaga","year":"1997","journal-title":"Neurosci. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Calvani, M., and Bruno, G. (2020). Beta3-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041420"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"R1496","DOI":"10.1152\/ajpregu.2000.278.6.R1496","article-title":"Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo","volume":"278","author":"Takahashi","year":"2000","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1172\/JCI0214924","article-title":"Cyclooxygenase-1-selective inhibition prolongs gestation in mice without adverse effects on the ductus arteriosus","volume":"110","author":"Loftin","year":"2002","journal-title":"J. Clin. Investg."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1161\/CIRCULATIONAHA.113.004726","article-title":"Prostaglandin E2 inhibits elastogenesis in the ductus arteriosus via EP4 signaling","volume":"129","author":"Yokoyama","year":"2014","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1053\/j.semperi.2011.09.018","article-title":"Mechanisms for ductus arteriosus closure","volume":"36","author":"Coceani","year":"2012","journal-title":"Semin. Perinatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/s13224-014-0591-7","article-title":"Constriction of the Umbilical Cord by an Amniotic Band Leading to Fetal Demise","volume":"65","author":"Patra","year":"2015","journal-title":"J. Obstet. Gynaecol. India"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1210\/jc.2004-0233","article-title":"Beta3-adrenoceptor is the predominant beta-adrenoceptor subtype in human myometrium and its expression is up-regulated in pregnancy","volume":"90","author":"Rouget","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/j.1476-5381.2009.00186.x","article-title":"Role of alpha 1-and beta 3-adrenoceptors in the modulation by SR59230A of the effects of MDMA on body temperature in the mouse","volume":"158","author":"Bexis","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_43","first-page":"44","article-title":"Rabbit myometrial adrenergic sensitivity is increased by estrogen bur is independent of changes in alpha adrenoceptor concentration","volume":"240","author":"Riemer","year":"1986","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.3389\/fimmu.2020.02098","article-title":"\u03b23-Adrenoceptors as Putative Regulator of Immune Tolerance in Cancer and Pregnancy","volume":"11","author":"Calvani","year":"2020","journal-title":"Front. Immunol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/12\/2625\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:41:58Z","timestamp":1760179318000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/12\/2625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,7]]},"references-count":44,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["cells9122625"],"URL":"https:\/\/doi.org\/10.3390\/cells9122625","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,7]]}}}