{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T18:15:54Z","timestamp":1783016154163,"version":"3.54.6"},"reference-count":56,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,20]],"date-time":"2022-03-20T00:00:00Z","timestamp":1647734400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Peripheral arterial disease (PAD) is characterised by accelerated arterial calcification and impairment in angiogenesis. Studies implicate vascular calcification as a contributor to PAD, but the mechanisms remain unclear. We aimed to determine the effect of calcification on ischaemia-driven angiogenesis. Human coronary artery endothelial cells (ECs) were treated with calcification medium (CM: CaCl2 2.7 mM, Na2PO4 2.0 mM) for 24 h and exposed to normoxia (5% CO2) or hypoxia (1.2% O2; 5% CO2 balanced with N2). In normoxia, CM significantly inhibited tubule formation and migration and upregulated calcification markers of ALP, BMP2, and Runx2. CM elevated levels of calcification-protective gene OPG, demonstrating a compensatory mechanism by ECs. CM failed to induce pro-angiogenic regulators VEGFA and HIF-1\u03b1 in hypoxia and further suppressed the phosphorylation of endothelial nitric oxide synthase (eNOS) that is essential for vascular function. In vivo, osteoprotegerin-deficient mice (OPG\u2212\/\u2212), a calcification model, were subjected to hind-limb ischaemia (HLI) surgery. OPG\u2212\/\u2212 mice displayed elevated serum alkaline phosphatase (ALP) activity compared to wild-type controls. OPG\u2212\/\u2212 mice experienced striking reductions in blood-flow reperfusion in both 8-week-old and 6-month-old mice post-HLI. This coincided with significant impairment in tissue ischaemia and reduced limb function as assessed by clinical scoring (Tarlov). This study demonstrated for the first time that a pro-calcific environment is detrimental to ischaemia-driven angiogenesis. The degree of calcification in patients with PAD can often be a limiting factor with the use of standard therapies. These highly novel findings require further studies for full elucidation of the mechanisms involved and have implications for the development of therapies to suppress calcification in PAD.<\/jats:p>","DOI":"10.3390\/ijms23063363","type":"journal-article","created":{"date-parts":[[2022,3,20]],"date-time":"2022-03-20T21:30:14Z","timestamp":1647811814000},"page":"3363","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pro-Calcific Environment Impairs Ischaemia-Driven Angiogenesis"],"prefix":"10.3390","volume":"23","author":[{"given":"Jocelyne","family":"Mulangala","sequence":"first","affiliation":[{"name":"Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma J.","family":"Akers","sequence":"additional","affiliation":[{"name":"Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9992-1181","authenticated-orcid":false,"given":"Emma L.","family":"Solly","sequence":"additional","affiliation":[{"name":"Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panashe M.","family":"Bamhare","sequence":"additional","affiliation":[{"name":"Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura A.","family":"Wilsdon","sequence":"additional","affiliation":[{"name":"Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan K. P.","family":"Wong","sequence":"additional","affiliation":[{"name":"Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia"},{"name":"Faculty of Medicine and Health, School of Medicine, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1875-4882","authenticated-orcid":false,"given":"Joanne T. M.","family":"Tan","sequence":"additional","affiliation":[{"name":"Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0682-8760","authenticated-orcid":false,"given":"Christina A.","family":"Bursill","sequence":"additional","affiliation":[{"name":"Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Vascular Research Centre, Heart Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen J.","family":"Nicholls","sequence":"additional","affiliation":[{"name":"Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Melbourne, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda A.","family":"Di Bartolo","sequence":"additional","affiliation":[{"name":"Faculty of Medicine and Health, School of Medicine, The University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/S0140-6736(01)06351-6","article-title":"Peripheral arterial disease","volume":"358","author":"Ouriel","year":"2001","journal-title":"Lancet"},{"key":"ref_2","first-page":"397","article-title":"Peripheral arterial disease Diagnosis and management in general practice","volume":"42","author":"Au","year":"2013","journal-title":"Aust. Fam. Physician"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejvs.2004.03.021","article-title":"Therapeutic angiogenesis in peripheral arterial disease: Can biotechnology produce an effective collateral circulation?","volume":"28","author":"Collinson","year":"2004","journal-title":"Eur. J. Vasc. Endovasc. Surg. Off. J. Eur. Soc. Vasc. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1161\/CIRCRESAHA.116.303849","article-title":"Epidemiology of peripheral artery disease","volume":"116","author":"Criqui","year":"2015","journal-title":"Circ. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1161\/CIRCULATIONAHA.105.593442","article-title":"Peripheral arterial disease: Morbidity and mortality implications","volume":"114","author":"Golomb","year":"2006","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1001\/jama.286.11.1317","article-title":"PEripheral arterial disease detection, awareness, and treatment in primary care","volume":"286","author":"Hirsch","year":"2001","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/74651","article-title":"Mechanisms of angiogenesis and arteriogenesis","volume":"6","author":"Carmeliet","year":"2000","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1161\/ATVBAHA.116.306717","article-title":"Medial Arterial Calcification: An Overlooked Player in Peripheral Arterial Disease","volume":"36","author":"Ho","year":"2016","journal-title":"Arter. Thromb Vasc Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1161\/ATVBAHA.121.316252","article-title":"Medial Arterial Calcification: A Significant and Independent Contributor of Peripheral Artery Disease","volume":"42","year":"2022","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.jvs.2017.06.086","article-title":"Association of arterial calcification with chronic limb ischemia in patients with peripheral artery disease","volume":"67","author":"Zettervall","year":"2018","journal-title":"J. Vasc. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","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. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1038\/35025220","article-title":"Angiogenesis in cancer and other diseases","volume":"407","author":"Carmeliet","year":"2000","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1093\/cvr\/cvv104","article-title":"The role of high-density lipoproteins in the regulation of angiogenesis","volume":"106","author":"Tan","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1681\/ASN.2008070692","article-title":"Vascular Calcification: The Killer of Patients with Chronic Kidney Disease","volume":"20","author":"Mizobuchi","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1161\/CIRCRESAHA.110.234914","article-title":"Arterial calcification in chronic kidney disease: Key roles for calcium and phosphate","volume":"109","author":"Shanahan","year":"2011","journal-title":"Circ. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1134\/S0006297908070031","article-title":"Mechanisms of angiogenesis","volume":"73","author":"Karamysheva","year":"2008","journal-title":"Biochem. Biokhimiia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2174\/157489206775246502","article-title":"Intracellular calcium, endothelial cells and angiogenesis","volume":"1","author":"Munaron","year":"2006","journal-title":"Recent Pat. Anti-Cancer Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1101\/gad.12.9.1260","article-title":"Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification","volume":"12","author":"Bucay","year":"1998","journal-title":"Genes Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.atherosclerosis.2012.10.060","article-title":"Towards a more relevant hind limb model of muscle ischaemia","volume":"227","author":"Lotfi","year":"2013","journal-title":"Atherosclerosis"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1016\/j.jvs.2012.04.067","article-title":"Toward a mouse model of hind limb ischemia to test therapeutic angiogenesis","volume":"56","author":"Brenes","year":"2012","journal-title":"J. Vasc. Surg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1096\/fj.201700617R","article-title":"VEGFR2 is activated by high-density lipoproteins and plays a key role in the proangiogenic action of HDL in ischemia","volume":"32","author":"Cannizzo","year":"2018","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1016\/j.jacc.2005.12.054","article-title":"The relationship between plasma osteoprotegerin levels and coronary artery calcification in uncomplicated type 2 diabetic subjects","volume":"47","author":"Anand","year":"2006","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1161\/01.ATV.0000236428.91125.e6","article-title":"Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE\u2212\/\u2212 mice","volume":"26","author":"Bennett","year":"2006","journal-title":"Arter. Throm. Vasc. Biol."},{"key":"ref_24","first-page":"3162","article-title":"Osteoprotegerin Serum Levels in Men: Correlation with Age, Estrogen, and Testosterone Status1","volume":"86","author":"Szulc","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1681\/ASN.2011121191","article-title":"Mechanistic insights into vascular calcification in CKD","volume":"24","author":"Shroff","year":"2013","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1161\/01.RES.0000163634.51301.0d","article-title":"Angiogenesis and pericytes in the initiation of ectopic calcification","volume":"96","author":"Collett","year":"2005","journal-title":"Circ. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1182\/blood-2006-06-029298","article-title":"Receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) increases vascular permeability: Impaired permeability and angiogenesis in eNOS-deficient mice","volume":"109","author":"Min","year":"2007","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6799","DOI":"10.1074\/jbc.M109434200","article-title":"TNF-related activation-induced cytokine (TRANCE) induces angiogenesis through the activation of Src and phospholipase C (PLC) in human endothelial cells","volume":"277","author":"Kim","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1007\/s00018-007-7104-0","article-title":"RANKL, RANK, osteoprotegerin: Key partners of osteoimmunology and vascular diseases","volume":"64","author":"Lamoureux","year":"2007","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1084\/jem.186.12.2075","article-title":"TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor","volume":"186","author":"Wong","year":"1997","journal-title":"J. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"39548","DOI":"10.1074\/jbc.M300539200","article-title":"Vascular endothelial growth factor up-regulates expression of receptor activator of NF-kappa B (RANK) in endothelial cells. Concomitant increase of angiogenic responses to RANK ligand","volume":"278","author":"Min","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S0925-4773(01)00428-2","article-title":"Tissue specific regulation of VEGF expression during bone development requires Cbfa1\/Runx2","volume":"106","author":"Zelzer","year":"2001","journal-title":"Mech. Dev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.pharmthera.2017.08.015","article-title":"The role of osteoprotegerin in the crosstalk between vessels and bone: Its potential utility as a marker of cardiometabolic diseases","volume":"182","author":"Rochette","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s10456-013-9337-x","article-title":"Mechanistic study of the proangiogenic effect of osteoprotegerin","volume":"16","author":"Poirier","year":"2013","journal-title":"Angiogenesis"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1002\/ijc.21606","article-title":"Osteoprotegerin (OPG)\u2014A potential new role in the regulation of endothelial cell phenotype and tumour angiogenesis?","volume":"118","author":"Cross","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1111\/j.1538-7836.2011.04207.x","article-title":"Osteoprotegerin, a new actor in vasculogenesis, stimulates endothelial colony-forming cells properties","volume":"9","author":"Heymann","year":"2011","journal-title":"J. Thromb. Haemost. JTH"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"20959","DOI":"10.1074\/jbc.C000290200","article-title":"Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells","volume":"275","author":"Malyankar","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s10456-008-9127-z","article-title":"Osteoprotegerin and RANKL differentially regulate angiogenesis and endothelial cell function","volume":"12","author":"McGonigle","year":"2009","journal-title":"Angiogenesis"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Di Bartolo, B.A., Cartland, S.P., Harith, H.H., Bobryshev, Y.V., Schoppet, M., and Kavurma, M.M. (2013). TRAIL-deficiency accelerates vascular calcification in atherosclerosis via modulation of RANKL. PLoS ONE, 8.","DOI":"10.1371\/annotation\/9732ca63-7532-4b92-8d6e-65c0863f25aa"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1210\/endo.138.7.5275","article-title":"Anabolic effects of 1,25-dihydroxyvitamin D3 on osteoblasts are enhanced by vascular endothelial growth factor produced by osteoblasts and by growth factors produced by endothelial cells","volume":"138","author":"Wang","year":"1997","journal-title":"Endocrinology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S0092-8674(00)80257-3","article-title":"Osf2\/Cbfa1: A transcriptional activator of osteoblast differentiation","volume":"89","author":"Ducy","year":"1997","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/S0092-8674(00)80258-5","article-title":"Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts","volume":"89","author":"Komori","year":"1997","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3582","DOI":"10.1002\/jcb.23289","article-title":"Physical and functional interactions between Runx2 and HIF-1alpha induce vascular endothelial growth factor gene expression","volume":"112","author":"Kwon","year":"2011","journal-title":"J. Cell. Biochem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"14760","DOI":"10.1074\/jbc.M112.340232","article-title":"Runx2 Protein Stabilizes Hypoxia-inducible Factor-1\u03b1 through Competition with von Hippel-Lindau Protein (pVHL) and Stimulates Angiogenesis in Growth Plate Hypertrophic Chondrocytes","volume":"287","author":"Lee","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_45","first-page":"4994","article-title":"Runt-related gene 2 in endothelial cells: Inducible expression and specific regulation of cell migration and invasion","volume":"61","author":"Sun","year":"2001","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"C1162","DOI":"10.1152\/ajpcell.00533.2008","article-title":"Chronic hypoxia attenuates VEGF signaling and angiogenic responses by downregulation of KDR in human endothelial cells","volume":"296","author":"Hein","year":"2009","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1161\/CIRCRESAHA.113.301792","article-title":"A role for the endothelium in vascular calcification","volume":"113","author":"Yao","year":"2013","journal-title":"Circ. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/s13670-013-0063-4","article-title":"Cardiovascular Calcifications in Old Age: Mechanisms and Clinical Implications","volume":"2","author":"Giallauria","year":"2013","journal-title":"Curr. Transl. Geriatr. Exp. Gerontol. Rep."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1038\/sj.ki.5001899","article-title":"Bisphosphonates prevent experimental vascular calcification: Treat the bone to cure the vessels?","volume":"70","author":"Persy","year":"2006","journal-title":"Kidney Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1136\/bjophthalmol-2013-303355","article-title":"Pro-inflammatory and anti-angiogenic effects of bisphosphonates on human cultured retinal pigment epithelial cells","volume":"97","author":"Or","year":"2013","journal-title":"Br. J. Ophthalmol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s00784-009-0365-2","article-title":"Bisphosphonates: Restrictions for vasculogenesis and angiogenesis: Inhibition of cell function of endothelial progenitor cells and mature endothelial cells in vitro","volume":"15","author":"Ziebart","year":"2011","journal-title":"Clin. Oral Investig."},{"key":"ref_52","first-page":"6538","article-title":"Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats","volume":"62","author":"Fournier","year":"2002","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1161\/CIRCULATIONAHA.107.707380","article-title":"Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr(-\/-) mice","volume":"117","author":"Morony","year":"2008","journal-title":"Circulation"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1084\/jem.192.4.463","article-title":"Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis","volume":"192","author":"Min","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1038\/nprot.2009.185","article-title":"Evaluation of postnatal arteriogenesis and angiogenesis in a mouse model of hind-limb ischemia","volume":"4","author":"Limbourg","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_56","first-page":"1110","article-title":"A review on angiogenesis and its assays","volume":"15","author":"Tahergorabi","year":"2012","journal-title":"Iran. J. Basic Med. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/6\/3363\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:40:01Z","timestamp":1760136001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/6\/3363"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,20]]},"references-count":56,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ijms23063363"],"URL":"https:\/\/doi.org\/10.3390\/ijms23063363","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,20]]}}}