{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T23:51:53Z","timestamp":1774569113785,"version":"3.50.1"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T00:00:00Z","timestamp":1686700800000},"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. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Calcification of soft tissues is a common age-related pathology that primarily occurs within vascular tissue. The mechanisms underlying pathological calcification in humans and tissue specificity of the process is still poorly understood. Previous studies examined calcified tissues on one to one basis, thus preventing comparison of deregulated pathways across tissues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Purpose<\/jats:title><jats:p>This study aimed to establish common and tissue-specific changes associated with calcification in aorta, artery tibial, coronary artery and pituitary gland in subjects from the Genotype-Tissue Expression (GTEx) dataset using its RNA sequencing and histological data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used publicly available data from the GTEx database <jats:uri>https:\/\/gtexportal.org\/home\/aboutGTEx<\/jats:uri>. All GTEx tissue samples were derived by the GTEx consorcium from deceased donors, with age from 20 to 79, both men and women. GTEx study authorization was obtained <jats:italic>via<\/jats:italic> next-of-kin consent for the collection and banking of de-identified tissue samples for scientific research. Hematoxylin and eosin (H&amp;amp;E) staining of arteries were manually graded based on the presence of calcification on a scale from zero to four, where zero designates absence of calcification and four designates severe calcification. Samples with fat contamination and mislabeled tissues were excluded, which left 430 aorta, 595 artery tibial, 124 coronary artery, and 283 pituitary samples for downstream gene expression analysis. Transcript levels of protein-coding genes were associated with calcification grade using sex, age bracket and cause of death as covariates, and tested for pathway enrichment using gene set enrichment analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified calcification deposits in 28 (6.5%) aortas, 121 (20%), artery tibials, 54 (43%), coronary arteries, and 24 (8%) pituitary glands of GTEx subjects. We observed an age-dependent increase in incidence of calcification in all vascular tissues, but not in pituitary. Subjects with calcification in the artery tibial were significantly more likely to have calcification in the coronary artery (OR\u2009=\u20092.56, <jats:italic>p<\/jats:italic> =\u20096.3e-07). Markers of calcification previously established in preclinical and <jats:italic>in vitro<\/jats:italic> studies, e.g., <jats:italic>BMP2<\/jats:italic> and <jats:italic>RUNX2<\/jats:italic>, were deregulated in the calcified tibial and coronary arteries, confirming the relevance of these genes to human pathology. Differentially expressed genes associated with calcification poorly overlapped across tissues suggesting tissue-specific nuances in mechanisms of calcification. Nevertheless, calcified arteries unanimously down-regulated pathways of intracellular transport and up-regulated inflammatory pathways suggesting these as universal targets for pathological calcification. In particular, PD-1 and PD-L1 genes were up-regulated in calcified tissues but not in the blood of the same subjects, suggesting that localized inflammation contributes to pathological calcification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Pathological calcification is a prevalent disease of aging that shares little changes in expression in individual genes across tissues. However, our analysis suggests that it potentially can be targeted by alleviating local inflammation of soft tissues.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2023.1131548","type":"journal-article","created":{"date-parts":[[2023,6,14]],"date-time":"2023-06-14T05:40:02Z","timestamp":1686721202000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Comparative analysis of calcified soft tissues revealed shared deregulated pathways"],"prefix":"10.3389","volume":"15","author":[{"given":"Aminat Guseynovna","family":"Ibragimova","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaroslav Mikhailovich","family":"Stanishevskiy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexey Mikhaylovich","family":"Plakkhin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandr Vladimirovich","family":"Zubko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nidal Akhmedovich","family":"Darvish","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton Karenovich","family":"Koassary","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anastasia V.","family":"Shindyapina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1111\/jch.13135","article-title":"Hypertension and frailty in older adults","volume":"20","author":"Aprahamian","year":"2018","journal-title":"J. Clin. Hypertens. Greenwich Conn"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s12967-017-1190-z","article-title":"A novel role of cellular interactions in vascular calcification","volume":"15","author":"Bardeesi","year":"2017","journal-title":"J. Transl. Med."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"415","DOI":"10.3390\/nu10040415","article-title":"Is matrix Gla protein associated with vascular calcification? A systematic review","volume":"10","author":"Barrett","year":"2018","journal-title":"Nutrients"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.1016\/j.jacc.2020.07.056","article-title":"Intracranial arterial calcification: prevalence, risk factors, and consequences: JACC review topic of the week","volume":"76","author":"Bartstra","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1053\/rmed.1999.0716","article-title":"Pulmonary calcifications: a review","volume":"94","author":"Bendayan","year":"2000","journal-title":"Respir. Med."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1647","DOI":"10.2174\/0929867325666180716104159","article-title":"The role of matrix Gla protein (MGP) in vascular calcification","volume":"27","author":"Bj\u00f8rklund","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1001\/jamaneurol.2013.6223","article-title":"Intracranial carotid artery atherosclerosis and the risk of stroke in whites: the Rotterdam study","volume":"71","author":"Bos","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"S104","DOI":"10.1016\/j.jalz.2012.01.008","article-title":"Atherosclerotic calcification relates to cognitive function and to brain changes on magnetic resonance imaging","volume":"8","author":"Bos","year":"2012","journal-title":"Alzheimers Dement."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1161\/ATVBAHA.111.224709","article-title":"Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation","volume":"31","author":"Bu","year":"2011","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"3447","DOI":"10.1161\/STROKEAHA.111.618652","article-title":"Presence of intracranial artery calcification is associated with mortality and vascular events in patients with ischemic stroke after hospital discharge: a cohort study","volume":"42","author":"Bugnicourt","year":"2011","journal-title":"Stroke"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"708470","DOI":"10.3389\/fcvm.2021.708470","article-title":"Wnt signaling in vascular calcification","volume":"8","author":"Bundy","year":"2021","journal-title":"Front Cardiovasc Med."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.yexcr.2016.06.007","article-title":"WNT\/\u03b2-catenin signaling promotes VSMCs to osteogenic transdifferentiation and calcification through directly modulating Runx2 gene expression","volume":"345","author":"Cai","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1007\/s11914-015-0293-9","article-title":"Pathophysiology of vascular calcification","volume":"13","author":"Chen","year":"2015","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1161\/ATVBAHA.120.313791","article-title":"Transcriptional programming in arteriosclerotic disease: a multifaceted function of the Runx2 (runt-related transcription factor 2)","volume":"41","author":"Chen","year":"2021","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1093\/qjmed\/hcaa147","article-title":"Tracheobronchial calcification in a dialysis patient with metastatic pulmonary calcification","volume":"114","author":"Chuang","year":"2021","journal-title":"QJM"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1111\/j.1525-139X.2007.00265.x","article-title":"Vascular calcification--a new window on the cardiovascular system: role of agents used to manipulate skeletal integrity","volume":"20","author":"Covic","year":"2007","journal-title":"Semin. Dial."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"2938","DOI":"10.1161\/CIRCULATIONAHA.107.743161","article-title":"Vascular calcification: pathobiology of a multifaceted disease","volume":"117","author":"Demer","year":"2008","journal-title":"Circulation"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1161\/ATVBAHA.111.242594","article-title":"Inhibition of bone morphogenetic protein signaling reduces vascular calcification and atherosclerosis","volume":"32","author":"Derwall","year":"2012","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"11201","DOI":"10.1073\/pnas.1932554100","article-title":"Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads","volume":"100","author":"Doherty","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1007\/s00109-021-02037-7","article-title":"Vascular pathologies in chronic kidney disease: pathophysiological mechanisms and novel therapeutic approaches","volume":"99","author":"D\u00fcsing","year":"2021","journal-title":"J. Mol. Med. (Berl)"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/s0008-6363(01)00375-3","article-title":"Vascular calcification: expression patterns of the osteoblast-specific gene core binding factor alpha-1 and the protective factor matrix gla protein in human atherogenesis","volume":"52","author":"Engelse","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.xjon.2020.11.007","article-title":"Inflammatory and immune checkpoint markers are associated with the severity of aortic stenosis","volume":"5","author":"Erkhem-Ochir","year":"2020","journal-title":"JTCVS Open"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"703","DOI":"10.4103\/2230-8210.123573","article-title":"Pituitary calcification masquerading as pituitary apoplexy","volume":"17","author":"Garg","year":"2013","journal-title":"Ind. J Endocrinol. Metab."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1002\/acr.23106","article-title":"Association of Anti-Citrullinated peptide antibodies with coronary artery calcification in rheumatoid arthritis","volume":"69","author":"Geraldino-Pardilla","year":"2017","journal-title":"Arthritis Care Res."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"2974","DOI":"10.1172\/JCI31344","article-title":"Proatherogenic immune responses are regulated by the PD-1\/PD-L pathway in mice","volume":"117","author":"Gotsman","year":"2007","journal-title":"J. Clin. Invest."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"749","DOI":"10.1152\/physiolgenomics.00041.2016","article-title":"RNA expression profile of calcified bicuspid, tricuspid, and normal human aortic valves by RNA sequencing","volume":"48","author":"Guauque-Olarte","year":"2016","journal-title":"Physiol. Genomics"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"826744","DOI":"10.3389\/fcvm.2022.826744","article-title":"Identification of key non-coding RNAs and transcription factors in calcific aortic valve disease","volume":"9","author":"Guo","year":"2022","journal-title":"Front. Cardiovasc. Med."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"980","DOI":"10.3390\/ijms21030980","article-title":"The epigenetic landscape of vascular calcification: an integrative perspective","volume":"21","author":"Hou","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"6586","DOI":"10.1038\/s41598-020-63013-8","article-title":"Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease","volume":"10","author":"Jaminon","year":"2020","journal-title":"Sci. Rep."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1160\/TH03-08-0572","article-title":"Matrix Gla protein is associated with coronary artery calcification as assessed by electron-beam computed tomography","volume":"91","author":"Jono","year":"2004","journal-title":"Thromb. Haemost."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"e1546","DOI":"10.1097\/MD.0000000000001546","article-title":"High Agatston calcium score of intracranial carotid artery","volume":"94","author":"Kao","year":"2015","journal-title":"Medicine (Baltimore)"},{"key":"ref36","first-page":"1187","article-title":"No to shinkei =","volume":"38","author":"Kurisaka","year":"1986","journal-title":"Brain Nerve"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.3346\/jkms.2017.32.11.1738","article-title":"New aspects of vascular calcification: histone Deacetylases and beyond","volume":"32","author":"Kwon","year":"2017","journal-title":"J. Korean Med. Sci."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1093\/ehjci\/jeaa284","article-title":"Aortic and mitral valve calcification as markers of atherosclerotic cardiovascular disease risk","volume":"22","author":"Lamprea-Montealegre","year":"2021","journal-title":"Eur. Heart J. Cardiovasc. Imaging"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.1093\/eurheartj\/ehu163","article-title":"Medial vascular calcification revisited: review and perspectives","volume":"35","author":"Lanzer","year":"2014","journal-title":"Eur. Heart J."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"e017308","DOI":"10.1161\/JAHA.120.017308","article-title":"Vascular calcification as an Underrecognized risk factor for frailty in 1783 community-dwelling elderly individuals","volume":"9","author":"Lee","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"453","DOI":"10.4070\/kcj.2013.43.7.453","article-title":"Gender difference in bone loss and vascular calcification associated with age","volume":"43","author":"Lee","year":"2013","journal-title":"Korean Circ. J."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.matbio.2013.06.003","article-title":"Ectopic mineralization disorders of the extracellular matrix of connective tissue: molecular genetics and pathomechanisms of aberrant calcification","volume":"33","author":"Li","year":"2014","journal-title":"Matrix Biol. J. Int. Soc. Matrix Biol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.atherosclerosis.2007.11.031","article-title":"BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells","volume":"199","author":"Li","year":"2008","journal-title":"Atherosclerosis"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1016\/j.ajpath.2015.03.020","article-title":"Runx2 expression in smooth muscle cells is required for arterial medial calcification in mice","volume":"185","author":"Lin","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1908","DOI":"10.1161\/ATVBAHA.110.206185","article-title":"Paracrine osteogenic signals via bone morphogenetic protein-2 accelerate the atherosclerotic intimal calcification in vivo","volume":"30","author":"Nakagawa","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1253\/circj.cj-11-0395","article-title":"Cardiovascular calcification: an inflammatory disease","volume":"75","author":"New","year":"2011","journal-title":"Circ. J."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"174","DOI":"10.3389\/fcvm.2018.00174","article-title":"Cell-matrix interactions and Matricrine signaling in the pathogenesis of vascular calcification","volume":"5","author":"Ngai","year":"2018","journal-title":"Front. Cardiovasc. Med."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1002\/ajmg.b.32336","article-title":"Brain calcification process and phenotypes according to age and sex: lessons from SLC20A2, PDGFB, and PDGFRB mutation carriers. American journal of medical genetics","volume":"168","author":"Nicolas","year":"2015","journal-title":"Am. J. Med. Genet."},{"key":"ref50","first-page":"612","article-title":"Expression and localization of granzymes and perforin in human calcific aortic valve disease","volume":"24","author":"Ohukainen","year":"2015","journal-title":"J. Heart Valve Dis."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1093\/intimm\/dxm057","article-title":"PD-1 and PD-1 ligands: from discovery to clinical application","volume":"19","author":"Okazaki","year":"2007","journal-title":"Int. Immunol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.4103\/0366-6999.204931","article-title":"Vascular calcification: current genetics underlying this complex phenomenon","volume":"130","author":"P\u00e9rez-Hern\u00e1ndez","year":"2017","journal-title":"Chin. Med. J."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1161\/ATVBAHA.118.311576","article-title":"Multifaceted mechanisms of vascular calcification in aging","volume":"39","author":"Pescatore","year":"2019","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/pl00002027","article-title":"Biology of calcification in vascular cells: intima versus media","volume":"26","author":"Proudfoot","year":"2001","journal-title":"Herz"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"2203","DOI":"10.1111\/j.1582-4934.2010.01139.x","article-title":"Arterial calcifications","volume":"14","author":"Rennenberg","year":"2010","journal-title":"J. Cell. Mol. Med."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1186\/1750-1172-8-156","article-title":"Fahr\u2019s syndrome: literature review of current evidence","volume":"8","author":"Saleem","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"S213","DOI":"10.1111\/j.1447-0594.2010.00603","article-title":"Vascular aging: from molecular mechanism to clinical significance","volume":"10","author":"Sawabe","year":"2010","journal-title":"Geriatr Gerontol Int"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1007\/s10554-016-0920-2","article-title":"Adiposity assessed by anthropometric measures has a similar or greater predictive ability than dual-energy X-ray absorptiometry measures for abdominal aortic calcification in community-dwelling older adults","volume":"32","author":"Shang","year":"2016","journal-title":"Int. J. Cardiovasc. Imaging"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"e20149","DOI":"10.7759\/cureus.20149","article-title":"Coronary artery calcium score - a reliable Indicator of coronary artery disease?","volume":"13","author":"Shreya","year":"2021","journal-title":"Cureus"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1161\/CIRCRESAHA.112.267237","article-title":"Smooth muscle cell\u2013specific Runx2 deficiency inhibits vascular calcification","volume":"111","author":"Sun","year":"2012","journal-title":"Circ. Res."},{"key":"ref162","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.cca.2020.02.019","article-title":"PD-1\/PD-L1 in cardiovascular disease. Clinica chimica acta","volume":"505","author":"Sun","year":"2020","journal-title":"Int J. Clin. Chem."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1159\/000477901","article-title":"Intracranial internal carotid Artery Wall calcification in ischemic strokes treated with thrombolysis","volume":"79","author":"T\u00e1buas-Pereira","year":"2018","journal-title":"Eur. Neurol."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1111\/joim.12605","article-title":"Arterial ageing: from endothelial dysfunction to vascular calcification","volume":"281","author":"Tesauro","year":"2017","journal-title":"J. Intern. Med."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"30","DOI":"10.4103\/1319-2442.318546","article-title":"Prevalence of vascular calcification in chronic kidney disease stage 4 and 5 patients and its correlation with inflammatory markers of atherosclerosis","volume":"32","author":"Verma","year":"2021","journal-title":"Saudi J. Kidney Dis. Transpl."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"4274","DOI":"10.18632\/aging.102046","article-title":"The interplay between mineral metabolism, vascular calcification and inflammation in chronic kidney disease (CKD): challenging old concepts with new facts","volume":"11","author":"Viegas","year":"2019","journal-title":"Aging"},{"key":"ref68","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1093\/eurheartj\/ehv605","article-title":"Phosphate, pyrophosphate, and vascular calcification: a question of balance","volume":"38","author":"Villa-Bellosta","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1038\/nri3839","article-title":"Perforin and granzymes: function, dysfunction and human pathology","volume":"15","author":"Voskoboinik","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1189\/jlb.3MA0717-283","article-title":"The immunoinhibitory PD-1\/PD-L1 pathway in inflammatory blood vessel disease","volume":"103","author":"Weyand","year":"2018","journal-title":"J. Leukoc. Biol."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"115542","DOI":"10.1016\/j.bone.2020.115542","article-title":"The role of bone morphogenetic protein signaling in vascular calcification","volume":"141","author":"Yang","year":"2020","journal-title":"Bone"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"95","DOI":"10.3389\/fendo.2012.00095","article-title":"Mechanisms and clinical consequences of vascular calcification","volume":"3","author":"Zhu","year":"2012","journal-title":"Front. 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