{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:32:06Z","timestamp":1790937126350,"version":"4.1.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T00:00:00Z","timestamp":1647388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Parathyroid hormone is the main endocrine regulator of extracellular calcium and phosphorus levels. Secondary hyperparathyroidism\u2013induced endothelial dysfunction may be related to calcium homeostasis disorders. Here, we investigated the effects of parathyroid hormone on human umbilical vein endothelial cells (HUVECs) and characterized the involvement of store-operated Ca<jats:sup>2+<\/jats:sup> entry (SOCE) and the nuclear factor of activated T cells (NFAT) signaling pathway. We used immunoblot experiments to find that parathyroid hormone significantly enhanced the expression of the Orai1 channel, a type of channel mediating SOCE, SOCE activity, and Orai1-mediated proliferation of HUVECs but did not increase Orai2 and Orai3. RNA-seq was utilized to identify 1,655 differentially expressed genes (823 upregulated and 832 downregulated) in parathyroid hormone\u2013treated HUVECs as well as enhanced focal adhesion signaling and expression levels of two key genes, namely, COL1A1 and NFATC1. Increased protein and mRNA expression levels of COL1A1 and NFATC1 were confirmed by immunoblotting and quantitative RT-PCR, respectively. Cytosol and nuclei fractionation experiments and immunofluorescence methods were used to show that parathyroid hormone treatment increased NFATC1 nuclear translocation, which was inhibited by a calcineurin inhibitor (CsA), a selective calmodulin antagonist (W7), an Orai channel inhibitor (BTP2), or Orai1 small interfering RNA (siRNA) transfection. Parathyroid hormone also increased COL1A1 expression, cell migration, and proliferation of HUVECs. The PTH-induced increase in HUVEC migration and proliferation were inhibited by CsA, W7, BTP2, or COL1A1 siRNA transfection. These findings indicated that PTH increased Orai1 expression and Orai1-mediated SOCE, causing the nuclear translocation of NFATC1 to increase COL1A1 expression and COL1A1-mediated HUVEC migration and proliferation. These results suggest potential key therapeutic targets of Orai1 and the downstream calmodulin\/calcineurin\/NFATC1\/COL1A1 signaling pathway in parathyroid hormone\u2013induced endothelial dysfunction and shed light on underlying mechanisms that may be altered to prevent or treat secondary hyperparathyroidism\u2013associated cardiovascular disease.<\/jats:p>","DOI":"10.3389\/fcvm.2022.844671","type":"journal-article","created":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T04:56:01Z","timestamp":1647406561000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Parathyroid Hormone Promotes Human Umbilical Vein Endothelial Cell Migration and Proliferation Through Orai1-Mediated Calcium Signaling"],"prefix":"10.3389","volume":"9","author":[{"given":"Shuhao","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijie","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yv","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailong","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhangying","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lesha","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaile","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1053\/j.ajkd.2017.12.007","article-title":"Management of Traditional Cardiovascular Risk Factors in CKD: What Are the Data?","volume":"72","author":"Gregg","year":"2018","journal-title":"Am J Kidney Dis."},{"key":"B2","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1111\/1744-9987.12772","article-title":"Secondary Hyperparathyroidism: Pathogenesis and Latest Treatment","volume":"23","author":"Mizobuchi","year":"2019","journal-title":"Ther Apheresis Dialysis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/j.amjms.2017.02.008","article-title":"Secondary hyperparathyroidism in heart failure","volume":"354","author":"Morsy","year":"2017","journal-title":"Am J Med Sci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"18","DOI":"10.4158\/EP.14.1.18","article-title":"Management of secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease","volume":"14","author":"Andress","year":"2008","journal-title":"Endocrine Pract."},{"key":"B5","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1002\/cphy.c140071","article-title":"PTH and vitamin D","volume":"6","author":"Khundmiri","year":"2016","journal-title":"Compr Physiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1093\/cvr\/cvs092","article-title":"Aldosterone and parathyroid hormone: a precarious couple for cardiovascular disease","volume":"94","author":"Tomaschitz","year":"2012","journal-title":"Cardiovasc Res"},{"key":"B7","doi-asserted-by":"publisher","first-page":"49","DOI":"10.14797\/mdcj-13-2-49","article-title":"The Parathyroid Gland and Heart Disease","volume":"13","author":"Brown","year":"2017","journal-title":"Methodist Debakey Cardiovasc J."},{"key":"B8","doi-asserted-by":"publisher","first-page":"20849","DOI":"10.1074\/jbc.R116.735894","article-title":"Why Calcium? How calcium became the best communicator","volume":"291","author":"Carafoli","year":"2016","journal-title":"J Biol Chem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.ando.2020.02.005","article-title":"PTH and cardiovascular risk","volume":"82","author":"Gruson","year":"2021","journal-title":"Annales d'endocrinologie."},{"key":"B10","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.ando.2020.02.003","article-title":"Cardiovascular consequences of parathyroid disorders in adults","volume":"82","author":"Bollerslev","year":"2021","journal-title":"Annales d'endocrinologie."},{"key":"B11","doi-asserted-by":"publisher","first-page":"13784","DOI":"10.1523\/JNEUROSCI.1680-15.2015","article-title":"Store-operated calcium entry through orai is required for transcriptional maturation of the flight circuit in drosophila","volume":"35","author":"Pathak","year":"2015","journal-title":"J Neurosci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1007\/978-3-319-57732-6_24","article-title":"Cardiovascular and hemostatic disorders: SOCE in cardiovascular cells: emerging targets for therapeutic intervention","volume":"993","author":"Groschner","year":"2017","journal-title":"Adv Exp Med Biol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"424","DOI":"10.2337\/db18-0870","article-title":"Inhibition of NFAT signaling restores microvascular endothelial function in diabetic","volume":"69","author":"Garcia-Vaz","year":"2020","journal-title":"Mice Diabetes."},{"key":"B14","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1038\/nri1632","article-title":"NFAT proteins: key regulators of T-cell development and function","volume":"5","author":"Macian","year":"2005","journal-title":"Nat Rev Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"616","DOI":"10.2353\/ajpath.2009.081061","article-title":"Endothelial to mesenchymal transition via transforming growth factor-beta1\/Smad activation is associated with portal venous stenosis in idiopathic portal hypertension","volume":"175","author":"Kitao","year":"2009","journal-title":"Am J Pathol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"195","DOI":"10.3389\/fimmu.2020.00195","article-title":"The role of calcium-calcineurin-NFAT signaling pathway in health and autoimmune diseases","volume":"11","author":"Park","year":"2020","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"625633","DOI":"10.3389\/fonc.2020.625633","article-title":"Zinc finger protein CTCF Regulates Extracellular Matrix (ECM)-related gene expression associated with the Wnt signaling pathway in gastric cancer","volume":"10","author":"Liu","year":"2020","journal-title":"Front Oncol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3892\/mmr.2020.11648","article-title":"Activation of activin\/Smad2 and 3 signaling pathway and the potential involvement of endothelial-mesenchymal transition in the valvular damage due to rheumatic heart disease","volume":"23","author":"Xian","year":"2021","journal-title":"Mol Med Rep"},{"key":"B19","doi-asserted-by":"publisher","first-page":"103457","DOI":"10.1016\/j.bioorg.2019.103457","article-title":"COL1A1 and MZB1 as the hub genes influenced the proliferation, invasion, migration and apoptosis of rectum adenocarcinoma cells by weighted correlation network analysis","volume":"95","author":"Wu","year":"2020","journal-title":"Bioorg Chem"},{"key":"B20","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/s12964-020-00560-7","article-title":"TRPP2 and STIM1 form a microdomain to regulate store-operated Ca(2+) entry and blood vessel tone. Cell communication and signaling: CCS","volume":"18","author":"Guo","year":"2020"},{"key":"B21","doi-asserted-by":"publisher","first-page":"gfab184","DOI":"10.1093\/ndt\/gfab184","article-title":"Independent effects of secondary hyperparathyroidism and hyperphosphatemia on chronic kidney disease progression and cardiovascular events: an analysis from the NEFRONA cohort","author":"Bozic","year":"2021","journal-title":"Nephrol Dialysis Transplant"},{"key":"B22","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: a Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics (Oxford, England)."},{"key":"B23","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/s13045-017-0418-y","article-title":"Paxillin: a crossroad in pathological cell migration","volume":"10","author":"L\u00f3pez-Colom\u00e9","year":"2017","journal-title":"J Hematol Oncol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.mvr.2011.06.007","article-title":"Focal adhesion kinase regulation of mechanotransduction and its impact on endothelial cell functions","volume":"83","author":"Zebda","year":"2012","journal-title":"Microvasc Res."},{"key":"B25","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1101\/gad.311027.117","article-title":"Acetyl-CoA promotes glioblastoma cell adhesion and migration through Ca(2+)-NFAT signalling","volume":"32","author":"Lee","year":"2018","journal-title":"Genes Develop."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3646","DOI":"10.3390\/ijms21103646","article-title":"The role of Ca(2+)-NFATc1 signaling and its modulation on osteoclastogenesis","volume":"21","author":"Kang","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B27","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.theriogenology.2019.07.024","article-title":"COL1A1 affects apoptosis by regulating oxidative stress and autophagy in bovine cumulus cells","volume":"139","author":"Fu","year":"2019","journal-title":"Theriogenology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"21004","DOI":"10.1074\/jbc.M413191200","article-title":"Collagen alpha1(I) gene (COL1A1) is repressed by RFX family","volume":"280","author":"Sengupta","year":"2005","journal-title":"J Biol Chem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e002085","DOI":"10.1136\/bmjdrc-2020-002085","article-title":"Orai-vascular endothelial-cadherin signaling complex regulates high-glucose exposure-induced increased permeability of mouse aortic endothelial cells","volume":"9","author":"Wei","year":"2021","journal-title":"BMJ Open Diabetes Res Care"},{"key":"B30","doi-asserted-by":"publisher","first-page":"397","DOI":"10.18388\/abp.2005_3452","article-title":"Store-operated calcium entry in physiology and pathology of mammalian cells","volume":"52","author":"Targos","year":"2005","journal-title":"Acta Biochim Pol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1152\/physiol.00016.2018","article-title":"ORAI Channels as potential therapeutic targets in pulmonary hypertension","volume":"33","author":"Rode","year":"2018","journal-title":"Physiology (Bethesda, Md)."},{"key":"B32","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s11914-008-0014-8","article-title":"Parathyroid hormone and the cardiovascular system","volume":"6","author":"Fitzpatrick","year":"2008","journal-title":"Curr Osteoporos Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"29446","DOI":"10.1074\/jbc.M114.578492","article-title":"Stromal interaction molecule 1 (STIM1) and Orai1 mediate histamine-evoked calcium entry and nuclear factor of activated T-cells (NFAT) signaling in human umbilical vein endothelial cells","volume":"289","author":"Zhou","year":"2014","journal-title":"J Biol Chem."},{"key":"B34","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.bbrc.2019.12.035","article-title":"Oxidative stress facilitates cell death by inhibiting Orai1-mediated Ca(2+) entry in brain capillary endothelial cells","volume":"523","author":"Yamamura","year":"2020","journal-title":"Biochem Biophys Res Commun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/nature05097","article-title":"Calcineurin\/NFAT signalling regulates pancreatic beta-cell growth and function","volume":"443","author":"Heit","year":"2006","journal-title":"Nature."},{"key":"B36","doi-asserted-by":"publisher","first-page":"12757","DOI":"10.1002\/jcp.27896","article-title":"miR-133a-3p suppresses cell proliferation, migration, and invasion and promotes apoptosis in esophageal squamous cell carcinoma","volume":"234","author":"Yin","year":"2019","journal-title":"J Cell Physiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.bbcan.2014.07.009","article-title":"NFAT as cancer target: mission possible?","volume":"1846","author":"Qin","year":"2014","journal-title":"Biochimica et biophysica acta."},{"key":"B38","doi-asserted-by":"publisher","first-page":"383","DOI":"10.4161\/19336950.2014.951250","article-title":"Some assembly required: SOCE and Orai1 channels couple to NFAT transcriptional activity via calmodulin and calcineurin","volume":"8","author":"Braun","year":"2014","journal-title":"Channels (Austin, Tex)."},{"key":"B39","doi-asserted-by":"publisher","first-page":"576565","DOI":"10.3389\/fonc.2020.576565","article-title":"Detailed molecular mechanism and potential drugs for COL1A1 in carboplatin-resistant ovarian cancer","volume":"10","author":"Yang","year":"2020","journal-title":"Front Oncol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"7985","DOI":"10.2147\/OTT.S249667","article-title":"miR-133b Suppresses invasion and migration of gastric cancer cells via the COL1A1\/TGF-\u03b2 Axis","volume":"13","author":"Guo","year":"2020","journal-title":"Onco Targets Ther"},{"key":"B41","doi-asserted-by":"publisher","first-page":"850","DOI":"10.3389\/fonc.2020.00850","article-title":"CircCSPP1 functions as a ceRNA to promote colorectal carcinoma cell EMT and liver metastasis by upregulating COL1A1","volume":"10","author":"Wang","year":"2020","journal-title":"Front Oncol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"3137","DOI":"10.1093\/bioinformatics\/btx373","article-title":"FQC Dashboard: integrates FastQC results into a web-based, interactive, and extensible FASTQ quality control tool","volume":"33","author":"Brown","year":"2017","journal-title":"Bioinformatics (Oxford, England)."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat Commun."},{"key":"B44","doi-asserted-by":"publisher","first-page":"8971","DOI":"10.1002\/jcp.26841","article-title":"Lumichrome inhibits osteoclastogenesis and bone resorption through suppressing RANKL-induced NFAT activation and calcium signaling","volume":"233","author":"Liu","year":"2018","journal-title":"J Cell Physiol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/ki.2012.69","article-title":"Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease","volume":"82","author":"Torres","year":"2012","journal-title":"Kidney Int."}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.844671\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,16]],"date-time":"2022-03-16T04:56:05Z","timestamp":1647406565000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2022.844671\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,16]]},"references-count":45,"alternative-id":["10.3389\/fcvm.2022.844671"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2022.844671","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,16]]},"article-number":"844671"}}