{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T02:30:52Z","timestamp":1767839452902,"version":"3.49.0"},"reference-count":61,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,2,18]],"date-time":"2020-02-18T00:00:00Z","timestamp":1581984000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DARP","award":["DARP-Qin 2017"],"award-info":[{"award-number":["DARP-Qin 2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The formyl peptide receptor (FPR) family are a group of G-protein coupled receptors that play an important role in the regulation of inflammatory processes. It is well-established that activation of FPRs can have cardioprotective properties. Recently, more stable small-molecule FPR1\/2 agonists have been described, including both Compound 17b (Cmpd17b) and Compound 43 (Cmpd43). Both agonists activate a range of signals downstream of FPR1\/2 activation in human-engineered FPR-expressing cells, including ERK1\/2 and Akt. Importantly, Cmpd17b (but not Cmpd43) favours bias away from intracellular Ca2+ mobilisation in this context, which has been associated with greater cardioprotection in response to Cmpd17b over Cmpd43. However, it is unknown whether these FPR agonists impact vascular physiology and\/or elicit vasoprotective effects in the context of diabetes. First, we localized FPR1 and FPR2 receptors predominantly in vascular smooth muscle cells in the aortae of male C57BL\/6 mice. We then analysed the vascular effects of Cmpd17b and Cmpd43 on the aorta using wire-myography. Cmpd17b but not Cmpd43 evoked a concentration-dependent relaxation of the mouse aorta. Removal of the endothelium or blockade of endothelium-derived relaxing factors using pharmacological inhibitors had no effect on Cmpd17b-evoked relaxation, demonstrating that its direct vasodilator actions were endothelium-independent. In aortae primed with elevated K+ concentration, increasing concentrations of CaCl2 evoked concentration-dependent contraction that is abolished by Cmpd17b, suggesting the involvement of the inhibition of Ca2+ mobilisation via voltage-gated calcium channels. Treatment with Cmpd17b for eight weeks reversed endothelial dysfunction in STZ-induced diabetic aorta through the upregulation of vasodilator prostanoids. Our data indicate that Cmpd17b is a direct endothelium-independent vasodilator, and a vasoprotective molecule in the context of diabetes.<\/jats:p>","DOI":"10.3390\/ijms21041384","type":"journal-article","created":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T04:06:01Z","timestamp":1582085161000},"page":"1384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["The Novel Small-molecule Annexin-A1 Mimetic, Compound 17b, Elicits Vasoprotective Actions in Streptozotocin-induced Diabetic Mice"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7276-1405","authenticated-orcid":false,"given":"Sarah A","family":"Marshall","sequence":"first","affiliation":[{"name":"The Ritchie Centre, Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2169-2686","authenticated-orcid":false,"given":"Cheng Xue","family":"Qin","sequence":"additional","affiliation":[{"name":"Heart Failure Pharmacology, Baker Heart &amp; Diabetes Institute, Victoria 3004, Australia"},{"name":"Department of Pharmacology, University of Melbourne, Victoria 3010, Australia"},{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Jelinic","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy &amp; Microbiology, La Trobe University, Bundoora, Victoria 3086, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly","family":"O\u2019Sullivan","sequence":"additional","affiliation":[{"name":"School of BioSciences, The University of Melbourne, Victoria 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minh","family":"Deo","sequence":"additional","affiliation":[{"name":"Heart Failure Pharmacology, Baker Heart &amp; Diabetes Institute, Victoria 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesse","family":"Walsh","sequence":"additional","affiliation":[{"name":"Heart Failure Pharmacology, Baker Heart &amp; Diabetes Institute, Victoria 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0519-6765","authenticated-orcid":false,"given":"Mandy","family":"Li","sequence":"additional","affiliation":[{"name":"Heart Failure Pharmacology, Baker Heart &amp; Diabetes Institute, Victoria 3004, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura J","family":"Parry","sequence":"additional","affiliation":[{"name":"School of BioSciences, The University of Melbourne, Victoria 3010, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca H.","family":"Ritchie","sequence":"additional","affiliation":[{"name":"Heart Failure Pharmacology, Baker Heart &amp; Diabetes Institute, Victoria 3004, Australia"},{"name":"Department of Pharmacology, University of Melbourne, Victoria 3010, Australia"},{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1424-9694","authenticated-orcid":false,"given":"Chen Huei","family":"Leo","sequence":"additional","affiliation":[{"name":"School of BioSciences, The University of Melbourne, Victoria 3010, Australia"},{"name":"Science and Math Cluster, Singapore University of Technology &amp; Design, Singapore 487372, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1124\/pr.109.001578","article-title":"International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family","volume":"61","author":"Ye","year":"2009","journal-title":"Pharm. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"He, H.Q., and Ye, R.D. (2017). The formyl peptide receptors: Diversity of ligands and mechanism for recognition. Molecules, 22.","DOI":"10.3390\/molecules22030455"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.pharmthera.2014.11.012","article-title":"Cardioprotective potential of annexin-A1 mimetics in myocardial infarction","volume":"148","author":"Qin","year":"2015","journal-title":"Pharm. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1111\/j.1476-5381.2012.02176.x","article-title":"Reperfusion-induced myocardial dysfunction is prevented by endogenous annexin-A1 and its N-terminal-derived peptide Ac-ANX-A1(2-26)","volume":"168","author":"Qin","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0014-2999(03)01314-1","article-title":"Cardioprotective actions of an N-terminal fragment of annexin-1 in rat myocardium in vitro","volume":"461","author":"Ritchie","year":"2003","journal-title":"Eur. J. Pharm."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/sj.bjp.0706211","article-title":"Annexin-1 peptide Anx-1(2-26) protects adult rat cardiac myocytes from cellular injury induced by simulated ischaemia","volume":"145","author":"Ritchie","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4240","DOI":"10.1096\/fj.10-159913","article-title":"FPR2\/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis","volume":"24","author":"Maderna","year":"2010","journal-title":"FASEB J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1161\/CIRCULATIONAHA.115.020633","article-title":"Formyl-Peptide Receptor 2\/3\/Lipoxin A4 Receptor Regulates Neutrophil-Platelet Aggregation and Attenuates Cerebral Inflammation: Impact for Therapy in Cardiovascular Disease","volume":"133","author":"Vital","year":"2016","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1096\/fj.14-263160","article-title":"Targeting formyl peptide receptor 2 reduces leukocyte-endothelial interactions in a murine model of stroke","volume":"29","author":"Smith","year":"2015","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Peshavariya, H.M., Taylor, C.J., Goh, C., Liu, G.S., Jiang, F., Chan, E.C., and Dusting, G.J. (2013). Annexin peptide Ac2-26 suppresses TNFalpha-induced inflammatory responses via inhibition of Rac1-dependent NADPH oxidase in human endothelial cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060790"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/278456a0","article-title":"Anti-inflammatory steroids induce biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation","volume":"278","author":"Flower","year":"1979","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jelinic, M., Kahlberg, N., Leo, C.H., Ng, H.H., Rosli, S., Deo, M., Li, M., Finlayson, S., Walsh, J., and Parry, L.J. (2019). Annexin-A1 deficiency exacerabates pathological remodelling of the mesenteric vasculature in insulin-resistance but not insulin-deficiency. Br. J. Pharm.","DOI":"10.1111\/bph.14927"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5044","DOI":"10.1021\/jm900592h","article-title":"6-methyl-2,4-disubstituted pyridazin-3(2H)-ones: A novel class of small-molecule agonists for formyl peptide receptors","volume":"52","author":"Cilibrizzi","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3713","DOI":"10.1016\/j.bmcl.2006.04.068","article-title":"Potent hFPRL1 (ALXR) agonists as potential anti-inflammatory agents","volume":"16","author":"Burli","year":"2006","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14232","DOI":"10.1038\/ncomms14232","article-title":"Small-molecule-biased formyl peptide receptor agonist compound 17b protects against myocardial ischaemia-reperfusion injury in mice","volume":"8","author":"Qin","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e12464","DOI":"10.1111\/micc.12464","article-title":"From pregnancy to cardiovascular disease: Lessons from relaxin-deficient animals to understand relaxin actions in the vascular system","volume":"26","author":"Jelinic","year":"2019","journal-title":"Microcirculation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"R753","DOI":"10.1152\/ajpregu.00276.2017","article-title":"The peptide hormone relaxin: From bench to bedside","volume":"314","author":"Jelinic","year":"2018","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1111\/bph.13614","article-title":"Vascular actions of relaxin: Nitric oxide and beyond","volume":"174","author":"Leo","year":"2017","journal-title":"Br. J. Pharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1093\/bja\/aen074","article-title":"Endogenous antimicrobial peptide LL-37 induces human vasodilatation","volume":"100","author":"Berkestedt","year":"2008","journal-title":"Br. J. Anaesth."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1161\/01.CIR.0000140985.89766.CB","article-title":"Aspirin-triggered, cyclooxygenase-2-dependent lipoxin synthesis modulates vascular tone","volume":"110","author":"Hollenberg","year":"2004","journal-title":"Circulation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.ejphar.2014.11.026","article-title":"FPR2\/ALX activation reverses LPS-induced vascular hyporeactivity in aorta and increases survival in a pneumosepsis model","volume":"746","author":"Horewicz","year":"2015","journal-title":"Eur. J. Pharm."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1159\/000371490","article-title":"Lipoxin A4 mediates aortic contraction via RHOA\/RHO kinase, endothelial dysfunction and reactive oxygen species","volume":"51","author":"Wenceslau","year":"2014","journal-title":"J. Vasc. Res."},{"key":"ref_23","first-page":"297","article-title":"Formyl Peptide Receptor Activation Elicits Endothelial Cell Contraction and Vascular Leakage","volume":"7","author":"Wenceslau","year":"2016","journal-title":"Front. Pharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"92","DOI":"10.4239\/wjd.v2.i6.92","article-title":"Vascular dysfunction in diabetes: The endothelial progenitor cells as new therapeutic strategy","volume":"2","author":"Georgescu","year":"2011","journal-title":"World J. Diabetes"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.tips.2016.04.001","article-title":"Serelaxin: A novel therapeutic for vascular diseases","volume":"37","author":"Leo","year":"2016","journal-title":"Trends Pharm. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1161\/ATVBAHA.115.305530","article-title":"Acute hyperglycemia impairs vascular function in healthy and cardiometabolic diseased subjects: Systematic review and meta-analysis","volume":"35","author":"Loader","year":"2015","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.phrs.2012.07.010","article-title":"Endothelium-dependent nitroxyl-mediated relaxation is resistant to superoxide anion scavenging and preserved in diabetic rat aorta","volume":"66","author":"Leo","year":"2012","journal-title":"Pharm. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"H502","DOI":"10.1152\/ajpheart.01197.2009","article-title":"Short term type 1 diabetes alters the mechanism of endothelium-dependent relaxation in the rat carotid artery","volume":"299","author":"Leo","year":"2010","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.phrs.2016.03.011","article-title":"Serelaxin (recombinant human relaxin-2) prevents high glucose-induced endothelial dysfunction by ameliorating prostacyclin production in the mouse aorta","volume":"107","author":"Ng","year":"2016","journal-title":"Pharm. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1161\/01.CIR.0000012748.58444.08","article-title":"Mechanisms of increased vascular superoxide production in human diabetes mellitus: Role of NAD(P)H oxidase and endothelial nitric oxide synthase","volume":"105","author":"Guzik","year":"2002","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/S0735-1097(99)00547-1","article-title":"Endothelial vasodilator function is related to low-density lipoprotein particle size and low-density lipoprotein vitamin E content in type 1 diabetes","volume":"35","author":"Luo","year":"2000","journal-title":"J. Am. Coll Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s11154-010-9134-4","article-title":"Endothelial dysfunction in diabetes mellitus: Molecular mechanisms and clinical implications","volume":"11","author":"Tabit","year":"2010","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1097\/FJC.0000000000000180","article-title":"Flavonols in the Prevention of Diabetes-induced Vascular Dysfunction","volume":"65","author":"Leo","year":"2015","journal-title":"J. Cardiovasc. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3389\/fphar.2018.00501","article-title":"Relaxin as a Therapeutic Target for the Cardiovascular Complications of Diabetes","volume":"9","author":"Ng","year":"2018","journal-title":"Front. Pharm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0014-5793(88)80384-3","article-title":"Mesenteric vascular responses to i.v. administration of lipoxin A4 and lipoxin B4 in the conscious rat","volume":"232","author":"Feuerstein","year":"1988","journal-title":"FEBS Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"C799","DOI":"10.1152\/ajpcell.1995.268.4.C799","article-title":"Physiological roles and properties of potassium channels in arterial smooth muscle","volume":"268","author":"Nelson","year":"1995","journal-title":"Am. J. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1139\/y05-016","article-title":"Ion channels in smooth muscle: Regulators of intracellular calcium and contractility","volume":"83","author":"Thorneloe","year":"2005","journal-title":"Can. J. Physiol. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1385\/CBB:33:3:275","article-title":"Calcium signaling and annexins","volume":"33","author":"Hawkins","year":"2000","journal-title":"Cell Biochem. Biophys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1159\/000174250","article-title":"Voltage-dependent Ca2+ channels in arterial smooth muscle cells","volume":"20","author":"Gollasch","year":"1997","journal-title":"Kidney Blood Press Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.2337\/db17-1317","article-title":"Lipoxins Protect Against Inflammation in Diabetes-Associated Atherosclerosis","volume":"67","author":"Brennan","year":"2018","journal-title":"Diabetes"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.bcp.2016.12.019","article-title":"1,4-Anhydro-4-seleno-d-talitol (SeTal) protects endothelial function in the mouse aorta by scavenging superoxide radicals under conditions of acute oxidative stress","volume":"128","author":"Ng","year":"2017","journal-title":"Biochem. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.phrs.2016.06.025","article-title":"Adverse vascular remodelling is more sensitive than endothelial dysfunction to hyperglycaemia in diabetic rat mesenteric arteries","volume":"111","author":"Kahlberg","year":"2016","journal-title":"Pharm. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/j.1476-5381.2010.01023.x","article-title":"Impairment of both nitric oxide-mediated and EDHF-type relaxation in small mesenteric arteries from rats with streptozotocin-induced diabetes","volume":"162","author":"Leo","year":"2011","journal-title":"Br J Pharm."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ejphar.2011.03.018","article-title":"3\u2019,4\u2019-dihydroxyflavonol restores endothelium dependent relaxation in small mesenteric artery from rats with type 1 and type 2 diabetes","volume":"659","author":"Leo","year":"2011","journal-title":"Eur. J. Pharm."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Leo, C.H., Hart, J.L., and Woodman, O.L. (2011). 3\u2019,4\u2019-dihydroxyflavonol reduces superoxide and improves nitric oxide function in diabetic rat mesenteric arteries. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020813"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"39604","DOI":"10.1038\/srep39604","article-title":"Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes","volume":"7","author":"Ng","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1007\/s00125-017-4469-y","article-title":"Annexin A1 attenuates microvascular complications through restoration of Akt signalling in a murine model of type 1 diabetes","volume":"61","author":"Purvis","year":"2018","journal-title":"Diabetologia"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Qin, C.X., Anthonisz, J., Leo, C.H., Kahlberg, N., Velagic, A., Li, M., Jap, E., Woodman, O.L., Parry, L.J., and Horowitz, J.D. (2019). NO\u2022 resistance, induced in the myocardium by diabetes is circumvented by the NO redox sibling, nitroxyl. Antioxid. Redox Signal.","DOI":"10.1089\/ars.2018.7706"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Leo, C.H., Ng, H.H., Marshall, S.A., Jelinic, M., Rupasinghe, T., Qin, C., Roessner, U., Ritchie, R.H., Tare, M., and Parry, L.J. (2019). Relaxin reduces endothelium-derived vasoconstriction in hypertension: Revealing new therapeutic insights. Br. J. Pharm.","DOI":"10.1111\/bph.14858"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.bbrc.2012.09.125","article-title":"Green tea inhibits cycolooxygenase-2 in non-small cell lung cancer cells through the induction of Annexin-1","volume":"427","author":"Lu","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/sj.bjp.0706390","article-title":"Acetylcholine-induced endothelium-dependent contractions in the SHR aorta: The Janus face of prostacyclin","volume":"146","author":"Gluais","year":"2005","journal-title":"Br. J. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"269","DOI":"10.3389\/fphar.2019.00269","article-title":"Cardioprotective actions of the annexin-A1 N-terminal peptide, Ac2-26, against myocardial infarction","volume":"10","author":"Qin","year":"2019","journal-title":"Front. Pharm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1096\/fj.13-233429","article-title":"Localization of relaxin receptors in arteries and veins, and region-specific increases in compliance and bradykinin-mediated relaxation after in vivo serelaxin treatment","volume":"28","author":"Jelinic","year":"2014","journal-title":"FASEB J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1111\/bph.13404","article-title":"Time-dependent activation of prostacyclin and nitric oxide pathways during continuous i.v. infusion of serelaxin (recombinant human H2 relaxin)","volume":"173","author":"Leo","year":"2016","journal-title":"Br. J. Pharm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e000493","DOI":"10.1161\/JAHA.113.000493","article-title":"Acute intravenous injection of serelaxin (recombinant human relaxin-2) causes rapid and sustained bradykinin-mediated vasorelaxation","volume":"3","author":"Leo","year":"2014","journal-title":"J. Am. Heart Assoc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1093\/biolre\/iox023","article-title":"Relaxin treatment reduces angiotensin II-induced vasoconstriction in pregnancy and protects against endothelial dysfunction","volume":"96","author":"Marshall","year":"2017","journal-title":"Biol. Reprod."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"R847","DOI":"10.1152\/ajpregu.00506.2015","article-title":"Relaxin deficiency attenuates pregnancy-induced adaptation of the mesenteric artery to angiotensin II in mice","volume":"310","author":"Marshall","year":"2016","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"H285","DOI":"10.1152\/ajpheart.00786.2014","article-title":"Increased superoxide production and altered nitric oxide-mediated relaxation in the aorta of young but not old male relaxin-deficient mice","volume":"309","author":"Ng","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3389\/fphar.2017.00141","article-title":"Serelaxin Treatment Reduces Oxidative Stress and Increases Aldehyde Dehydrogenase-2 to Attenuate Nitrate Tolerance","volume":"8","author":"Leo","year":"2017","journal-title":"Front. Pharm."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.ejphar.2017.05.005","article-title":"B7-33 replicates the vasoprotective functions of human relaxin-2 (serelaxin)","volume":"807","author":"Marshall","year":"2017","journal-title":"Eur. J. Pharm."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.2337\/db09-1456","article-title":"Cardiac-specific IGF-1 receptor transgenic expression protects against cardiac fibrosis and diastolic dysfunction in a mouse model of diabetic cardiomyopathy","volume":"59","author":"Huynh","year":"2010","journal-title":"Diabetes"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/4\/1384\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:58:54Z","timestamp":1760173134000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/4\/1384"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,18]]},"references-count":61,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["ijms21041384"],"URL":"https:\/\/doi.org\/10.3390\/ijms21041384","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,18]]}}}