{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T06:55:10Z","timestamp":1793170510774,"version":"4.5.0"},"reference-count":78,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T00:00:00Z","timestamp":1605830400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T00:00:00Z","timestamp":1605830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011199","name":"FP7 Ideas: European Research Council","doi-asserted-by":"publisher","award":["805201"],"award-info":[{"award-number":["805201"]}],"id":[{"id":"10.13039\/100011199","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"UKRI | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P02209X\/1"],"award-info":[{"award-number":["MR\/P02209X\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004789","name":"Oxford University | John Fell Fund, University of Oxford","doi-asserted-by":"publisher","award":["161\/061"],"award-info":[{"award-number":["161\/061"]}],"id":[{"id":"10.13039\/501100004789","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kenndy Trust for Rheumatology Research","award":["KENN 15 16 09"],"award-info":[{"award-number":["KENN 15 16 09"]}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["CRUKDF 0317\u2010AK"],"award-info":[{"award-number":["CRUKDF 0317\u2010AK"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015763","name":"Leukaemia UK","doi-asserted-by":"publisher","award":["2017\/JGF\/001"],"award-info":[{"award-number":["2017\/JGF\/001"]}],"id":[{"id":"10.13039\/100015763","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008134","name":"Office of the Royal Society","doi-asserted-by":"publisher","award":["RG170326"],"award-info":[{"award-number":["RG170326"]}],"id":[{"id":"10.13039\/501100008134","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wellcome","award":["202300\/Z\/16\/Z"],"award-info":[{"award-number":["202300\/Z\/16\/Z"]}]},{"name":"Wellcome","award":["100262Z\/12\/Z"],"award-info":[{"award-number":["100262Z\/12\/Z"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["EMBO J"],"published-print":{"date-parts":[[2021,1,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Age\u2010associated alterations of the hormone\u2010secreting endocrine system cause organ dysfunction and disease states. However, the cell biology of endocrine tissue ageing remains poorly understood. Here, we perform comparative 3D imaging to understand age\u2010related perturbations of the endothelial cell (EC) compartment in endocrine glands. Datasets of a wide range of markers highlight a decline in capillary and artery numbers, but not of perivascular cells in pancreas, testis and thyroid gland, with age in mice and humans. Further, angiogenesis and \u03b2\u2010cell expansion in the pancreas are coupled by a distinct age\u2010dependent subset of ECs. While this EC subpopulation supports pancreatic \u03b2 cells, it declines during ageing concomitant with increased expression of the gap junction protein Gja1. EC\u2010specific ablation of Gja1 restores \u03b2\u2010cell expansion in the aged pancreas. These results provide a proof of concept for understanding age\u2010related vascular changes and imply that therapeutic targeting of blood vessels may restore aged endocrine tissue function. This comprehensive data atlas offers over &gt;\u00a01,000 multicolour volumes for exploration and research in endocrinology, ageing, matrix and vascular biology.<\/jats:p>","DOI":"10.15252\/embj.2020105242","type":"journal-article","created":{"date-parts":[[2020,11,20]],"date-time":"2020-11-20T16:12:12Z","timestamp":1605888732000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Decreased blood vessel density and endothelial cell subset dynamics during ageing of the endocrine system"],"prefix":"10.1038","volume":"40","author":[{"given":"Junyu","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Lippo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Labella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sin Lih","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1937-4091","authenticated-orcid":false,"given":"Brian D","family":"Marsden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4983-6389","authenticated-orcid":false,"given":"Michael L","family":"Dustin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saravana K","family":"Ramasamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1911-5495","authenticated-orcid":false,"given":"Anjali P","family":"Kusumbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,20]]},"reference":[{"key":"BFEMBJ2020105242_CR1","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1111\/dom.13031","volume":"19","author":"KI Aamodt","year":"2017","unstructured":"Aamodt KI, Powers AC (2017) Signals in the pancreatic islet microenvironment influence \u03b2\u2010cell proliferation. Diabetes Obes Metab 19: 124\u2013136","journal-title":"Diabetes Obes Metab"},{"key":"BFEMBJ2020105242_CR2","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s12079-016-0352-8","volume":"10","author":"CS Abhinand","year":"2016","unstructured":"Abhinand CS, Raju R, Soumya SJ, Arya PS, Sudhakaran PR (2016) VEGF\u2010A\/VEGFR2 signaling network in endothelial cells relevant to angiogenesis. J Cell Commun Signal 10: 347\u2013354","journal-title":"J Cell Commun Signal"},{"key":"BFEMBJ2020105242_CR3","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/nrm2183","volume":"8","author":"RH Adams","year":"2007","unstructured":"Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8: 464\u2013478","journal-title":"Nat Rev Mol Cell Biol"},{"key":"BFEMBJ2020105242_CR4","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.pharmthera.2018.08.011","volume":"193","author":"DA Alagpulinsa","year":"2019","unstructured":"Alagpulinsa DA, Cao JJ, Sobell D, Poznansky MC (2019) Harnessing CXCL12 signaling to protect and preserve functional \u03b2\u2010cell mass and for cell replacement in type 1 diabetes. Pharmacol Ther 193: 63\u201374","journal-title":"Pharmacol Ther"},{"key":"BFEMBJ2020105242_CR5","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/nmeth.1896","volume":"9","author":"C Allan","year":"2012","unstructured":"Allan C, Burel J\u2010M, Moore J, Blackburn C, Linkert M, Loynton S, MacDonald D, Moore WJ, Neves C, Patterson A (2012) OMERO: flexible, model\u2010driven data management for experimental biology. Nat Methods 9: 245\u2013253","journal-title":"Nat Methods"},{"key":"BFEMBJ2020105242_CR6","doi-asserted-by":"crossref","first-page":"17612","DOI":"10.1073\/pnas.1414053111","volume":"111","author":"J Alma\u00e7a","year":"2014","unstructured":"Alma\u00e7a J, Molina J, Arrojo e Drigo R, Abdulreda MH, Jeon WB, Berggren P\u2010O, Caicedo A, Nam HG (2014) Young capillary vessels rejuvenate aged pancreatic islets. Proc Natl Acad Sci USA 111: 17612\u201317617","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFEMBJ2020105242_CR7","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/1471-2121-12-44","volume":"12","author":"FZ Asumda","year":"2011","unstructured":"Asumda FZ, Chase PB (2011) Age\u2010related changes in rat bone\u2010marrow mesenchymal stem cell plasticity. BMC Cell Biol 12: 44","journal-title":"BMC Cell Biol"},{"key":"BFEMBJ2020105242_CR8","doi-asserted-by":"crossref","DOI":"10.1126\/science.aal2379","volume":"357","author":"HG Augustin","year":"2017","unstructured":"Augustin HG, Koh GY (2017) Organotypic vasculature: from descriptive heterogeneity to functional pathophysiology. Science 357: eaal2379","journal-title":"Science"},{"key":"BFEMBJ2020105242_CR9","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41556-019-0439-6","volume":"22","author":"C Baccin","year":"2019","unstructured":"Baccin C, Al\u2010Sabah J, Velten L, Helbling PM, Gr\u00fcnschl\u00e4ger F, Hern\u00e1ndez\u2010Malmierca P, Nombela\u2010Arrieta C, Steinmetz LM, Trumpp A, Haas S (2019) Combined single\u2010cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat Cell Biol 22: 38\u201348","journal-title":"Nat Cell Biol"},{"key":"BFEMBJ2020105242_CR10","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s00268-006-0719-8","volume":"31","author":"N Ballian","year":"2007","unstructured":"Ballian N, Brunicardi FC (2007) Islet vasculature as a regulator of endocrine pancreas function. World J Surg 31: 705\u2013714","journal-title":"World J Surg"},{"key":"BFEMBJ2020105242_CR11","doi-asserted-by":"crossref","first-page":"2974","DOI":"10.2337\/db06-0690","volume":"55","author":"M Brissova","year":"2006","unstructured":"Brissova M, Shostak A, Shiota M, Wiebe PO, Poffenberger G, Kantz J, Chen Z, Carr C, Jerome WG, Chen J (2006) Pancreatic islet production of vascular endothelial growth factor\u2010a is essential for islet vascularization, revascularization, and function. Diabetes 55: 2974\u20132985","journal-title":"Diabetes"},{"key":"BFEMBJ2020105242_CR12","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1007\/s00335-015-9587-6","volume":"26","author":"J\u2010M Burel","year":"2015","unstructured":"Burel J\u2010M, Besson S, Blackburn C, Carroll M, Ferguson RK, Flynn H, Gillen K, Leigh R, Li S, Lindner D (2015) Publishing and sharing multi\u2010dimensional image data with OMERO. Mamm Genome 26: 441\u2013447","journal-title":"Mamm Genome"},{"key":"BFEMBJ2020105242_CR13","doi-asserted-by":"crossref","first-page":"102","DOI":"10.2337\/diabetes.52.1.102","volume":"52","author":"AE Butler","year":"2003","unstructured":"Butler AE, Janson J, Bonner\u2010Weir S, Ritzel R, Rizza RA, Butler PC (2003) \u03b2\u2010cell deficit and increased \u03b2\u2010cell apoptosis in humans with type 2 diabetes. Diabetes 52: 102\u2013110","journal-title":"Diabetes"},{"key":"BFEMBJ2020105242_CR14","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/nrc2791","volume":"10","author":"JM Butler","year":"2010","unstructured":"Butler JM, Kobayashi H, Rafii S (2010) Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10: 138\u2013146","journal-title":"Nat Rev Cancer"},{"key":"BFEMBJ2020105242_CR15","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nm0603-653","volume":"9","author":"P Carmeliet","year":"2003","unstructured":"Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9: 653\u2013660","journal-title":"Nat Med"},{"key":"BFEMBJ2020105242_CR16","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/S2213-8587(18)30028-7","volume":"6","author":"L Chaker","year":"2018","unstructured":"Chaker L, Cappola AR, Mooijaart SP, Peeters RP (2018) Clinical aspects of thyroid function during ageing. Lancet Diabetes Endocrinol 6: 733\u2013742","journal-title":"Lancet Diabetes Endocrinol"},{"key":"BFEMBJ2020105242_CR17","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/nature10502","volume":"478","author":"H Chen","year":"2011","unstructured":"Chen H, Gu X, Liu Y, Wang J, Wirt SE, Bottino R, Schorle H, Sage J, Kim SK (2011) PDGF signalling controls age\u2010dependent proliferation in pancreatic \u03b2\u2010cells. Nature 478: 349\u2013355","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR18","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1038\/nbt.4006","volume":"35","author":"DL Coutu","year":"2017","unstructured":"Coutu DL, Kokkaliaris KD, Kunz L, Schroeder T (2017) Three\u2010dimensional map of nonhematopoietic bone and bone\u2010marrow cells and molecules. Nat Biotechnol 35: 1202\u20131210","journal-title":"Nat Biotechnol"},{"key":"BFEMBJ2020105242_CR19","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1677\/joe.0.1710193","volume":"171","author":"VC Da Costa","year":"2001","unstructured":"Da Costa VC, Moreira D, Rosenthal D (2001) Thyroid function and aging: gender\u2010related differences. J Endocrinol 171: 193\u2013198","journal-title":"J Endocrinol"},{"key":"BFEMBJ2020105242_CR20","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.2337\/db11-1154","volume":"61","author":"C Demirci","year":"2012","unstructured":"Demirci C, Ernst S, Alvarez\u2010Perez JC, Rosa T, Valle S, Shridhar V, Casinelli GP, Alonso LC, Vasavada RC, Garc\u00eda\u2010Ocana A (2012) Loss of HGF\/c\u2010Met signaling in pancreatic \u03b2\u2010cells leads to incomplete maternal \u03b2\u2010cell adaptation and gestational diabetes mellitus. Diabetes 61: 1143\u20131152","journal-title":"Diabetes"},{"key":"BFEMBJ2020105242_CR21","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/nature09493","volume":"468","author":"B\u2010S Ding","year":"2010","unstructured":"Ding B\u2010S, Nolan DJ, Butler JM, James D, Babazadeh AO, Rosenwaks Z, Mittal V, Kobayashi H, Shido K, Lyden D (2010) Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration. Nature 468: 310\u2013315","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR22","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nature10783","volume":"481","author":"L Ding","year":"2012","unstructured":"Ding L, Saunders TL, Enikolopov G, Morrison SJ (2012) Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481: 457\u2013462","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR23","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1038\/nature12681","volume":"505","author":"B\u2010S Ding","year":"2014","unstructured":"Ding B\u2010S, Cao Z, Lis R, Nolan DJ, Guo P, Simons M, Penfold ME, Shido K, Rabbany SY, Rafii S (2014) Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505: 97\u2013102","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR24","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s00125-004-1336-4","volume":"47","author":"M Donath","year":"2004","unstructured":"Donath M, Halban PA (2004) Decreased beta\u2010cell mass in diabetes: significance, mechanisms and therapeutic implications. Diabetologia 47: 581\u2013589","journal-title":"Diabetologia"},{"key":"BFEMBJ2020105242_CR25","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nature02520","volume":"429","author":"Y Dor","year":"2004","unstructured":"Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic \u03b2\u2010cells are formed by self\u2010duplication rather than stem\u2010cell differentiation. Nature 429: 41\u201346","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR26","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.tem.2010.03.003","volume":"21","author":"D Eberhard","year":"2010","unstructured":"Eberhard D, Kragl M, Lammert E (2010) \u2018Giving and taking\u2019: endothelial and \u03b2\u2010cells in the islets of Langerhans. Trends Endocrinol Metab 21: 457\u2013463","journal-title":"Trends Endocrinol Metab"},{"key":"BFEMBJ2020105242_CR27","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a002576","volume":"1","author":"DA Goodenough","year":"2009","unstructured":"Goodenough DA, Paul DL (2009) Gap junctions. Cold Spring Harbor Perspect Biol 1: a002576","journal-title":"Cold Spring Harbor Perspect Biol"},{"key":"BFEMBJ2020105242_CR28","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s12565-010-0084-4","volume":"85","author":"J Gorczyca","year":"2010","unstructured":"Gorczyca J, Litwin JA, Pitynski K, Miodonski AJ (2010) Vascular system of human fetal pancreas demonstrated by corrosion casting and scanning electron microscopy. Anat Sci Int 85: 235\u2013240","journal-title":"Anat Sci Int"},{"key":"BFEMBJ2020105242_CR29","volume":"13","author":"ID Harris","year":"2011","unstructured":"Harris ID, Fronczak C, Roth L, Meacham RB (2011) Fertility and the aging male. Rev Urol 13: e184","journal-title":"Rev Urol"},{"key":"BFEMBJ2020105242_CR30","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrm3176","volume":"12","author":"SP Herbert","year":"2011","unstructured":"Herbert SP, Stainier DY (2011) Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nat Rev Mol Cell Biol 12: 551\u2013564","journal-title":"Nat Rev Mol Cell Biol"},{"key":"BFEMBJ2020105242_CR31","doi-asserted-by":"crossref","first-page":"750","DOI":"10.15252\/emmm.201607341","volume":"9","author":"JY Jang","year":"2017","unstructured":"Jang JY, Choi SY, Park I, Choe K, Kim P, Kim YK, Lee BJ, Hirashima M, Kubota Y, Park JW (2017) VEGFR2 but not VEGFR3 governs integrity and remodeling of thyroid angiofollicular unit in normal state and during goitrogenesis. EMBO Mol Med 9: 750\u2013769","journal-title":"EMBO Mol Med"},{"key":"BFEMBJ2020105242_CR32","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/s41422-018-0049-z","volume":"28","author":"D Jing","year":"2018","unstructured":"Jing D, Zhang S, Luo W, Gao X, Men Y, Ma C, Liu X, Yi Y, Bugde A, Zhou BO (2018) Tissue clearing of both hard and soft tissue organs with the PEGASOS method. Cell Res 28: 803\u2013818","journal-title":"Cell Res"},{"key":"BFEMBJ2020105242_CR33","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1002\/jemt.10256","volume":"60","author":"R Katoh","year":"2003","unstructured":"Katoh R (2003) Angiogenesis in endocrine glands: special reference to the expression of vascular endothelial growth factor. Microsc Res Tech 60: 181\u2013185","journal-title":"Microsc Res Tech"},{"key":"BFEMBJ2020105242_CR34","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/ng872","volume":"31","author":"RN Kulkarni","year":"2002","unstructured":"Kulkarni RN, Holzenberger M, Shih DQ, Ozcan U, Stoffel M, Magnuson MA, Kahn CR (2002) \u03b2\u2010cell\u2013specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter \u03b2\u2010cell mass. Nat Genet 31: 111\u2013115","journal-title":"Nat Genet"},{"key":"BFEMBJ2020105242_CR35","doi-asserted-by":"crossref","first-page":"3752","DOI":"10.1128\/MCB.25.9.3752-3762.2005","volume":"25","author":"JA Kushner","year":"2005","unstructured":"Kushner JA, Ciemerych MA, Sicinska E, Wartschow LM, Teta M, Long SY, Sicinski P, White MF (2005) Cyclins D2 and D1 are essential for postnatal pancreatic \u03b2\u2010cell growth. Mol Cell Biol 25: 3752\u20133762","journal-title":"Mol Cell Biol"},{"key":"BFEMBJ2020105242_CR36","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1172\/JCI64095","volume":"123","author":"JA Kushner","year":"2013","unstructured":"Kushner JA (2013) The role of aging upon \u03b2 cell turnover. J Clin Investig 123: 990\u2013995","journal-title":"J Clin Investig"},{"key":"BFEMBJ2020105242_CR37","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/nature13145","volume":"507","author":"AP Kusumbe","year":"2014","unstructured":"Kusumbe AP, Ramasamy SK, Adams RH (2014) Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507: 323\u2013328","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR38","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.jbo.2016.04.003","volume":"5","author":"AP Kusumbe","year":"2016","unstructured":"Kusumbe AP (2016) Vascular niches for disseminated tumour cells in bone. J Bone Oncol 5: 112\u2013116","journal-title":"J Bone Oncol"},{"key":"BFEMBJ2020105242_CR39","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nature17638","volume":"532","author":"AP Kusumbe","year":"2016","unstructured":"Kusumbe AP, Ramasamy SK, Itkin T, M\u00e4e MA, Langen UH, Betsholtz C, Lapidot T, Adams RH (2016) Age\u2010dependent modulation of vascular niches for haematopoietic stem cells. Nature 532: 380\u2013384","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR40","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/nrendo.2016.193","volume":"13","author":"P Le Tissier","year":"2017","unstructured":"Le Tissier P, Campos P, Lafont C, Roman\u00f2 N, Hodson DJ, Mollard P (2017) An updated view of hypothalamic\u2013vascular\u2013pituitary unit function and plasticity. Nat Rev Endocrinol 13: 257\u2013267","journal-title":"Nat Rev Endocrinol"},{"key":"BFEMBJ2020105242_CR41","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1038\/nprot.2009.150","volume":"4","author":"D\u2010S Li","year":"2009","unstructured":"Li D\u2010S, Yuan Y\u2010H, Tu H\u2010J, Liang Q\u2010L, Dai L\u2010J (2009) A protocol for islet isolation from mouse pancreas. Nat Protoc 4: 1649\u20131652","journal-title":"Nat Protoc"},{"key":"BFEMBJ2020105242_CR42","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature03080","volume":"432","author":"X Lu","year":"2004","unstructured":"Lu X, Le Noble F, Yuan L, Jiang Q, De Lafarge B, Sugiyama D, Br\u00e9ant C, Claes F, De Smet F, Thomas J\u2010L (2004) The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432: 179\u2013186","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR43","doi-asserted-by":"crossref","first-page":"S113","DOI":"10.2337\/dcS13-2008","volume":"36","author":"JJ Meier","year":"2013","unstructured":"Meier JJ, Bonadonna RC (2013) Role of reduced \u03b2\u2010cell mass versus impaired \u03b2\u2010cell function in the pathogenesis of type 2 diabetes. Diabetes Care 36: S113\u2013S119","journal-title":"Diabetes Care"},{"key":"BFEMBJ2020105242_CR44","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1016\/j.jhep.2015.05.011","volume":"63","author":"P Melgar\u2010Lesmes","year":"2015","unstructured":"Melgar\u2010Lesmes P, Edelman ER (2015) Monocyte\u2010endothelial cell interactions in the regulation of vascular sprouting and liver regeneration in mouse. J Hepatol 63: 917\u2013925","journal-title":"J Hepatol"},{"key":"BFEMBJ2020105242_CR45","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1111\/j.1742-1241.2007.01317.x","volume":"61","author":"M Miner","year":"2007","unstructured":"Miner M, Seftel A (2007) Testosterone and ageing: what have we learned since the Institute of Medicine report and what lies ahead? Int J Clin Pract 61: 622\u2013632","journal-title":"Int J Clin Pract"},{"key":"BFEMBJ2020105242_CR46","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/nrendo.2017.51","volume":"13","author":"A Nadal","year":"2017","unstructured":"Nadal A, Quesada I, Tuduri E, Nogueiras R, Alonso\u2010Magdalena P (2017) Endocrine\u2010disrupting chemicals and the regulation of energy balance. Nat Rev Endocrinol 13: 536\u2013546","journal-title":"Nat Rev Endocrinol"},{"key":"BFEMBJ2020105242_CR47","doi-asserted-by":"crossref","first-page":"172","DOI":"10.3389\/fnagi.2019.00172","volume":"11","author":"S Nizari","year":"2019","unstructured":"Nizari S, Carare RO, Romero IA, Hawkes CA (2019) 3D reconstruction of the neurovascular unit reveals differential loss of cholinergic innervation in the cortex and hippocampus of the adult mouse brain. Front Aging Neurosci 11: 172","journal-title":"Front Aging Neurosci"},{"key":"BFEMBJ2020105242_CR48","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.devcel.2013.06.017","volume":"26","author":"DJ Nolan","year":"2013","unstructured":"Nolan DJ, Ginsberg M, Israely E, Palikuqi B, Poulos MG, James D, Ding B\u2010S, Schachterle W, Liu Y, Rosenwaks Z (2013) Molecular signatures of tissue\u2010specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Dev Cell 26: 204\u2013219","journal-title":"Dev Cell"},{"key":"BFEMBJ2020105242_CR49","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/ncb3096","volume":"17","author":"S Rafii","year":"2015","unstructured":"Rafii S, Cao Z, Lis R, Siempos II, Chavez D, Shido K, Rabbany SY, Ding B\u2010S (2015) Platelet\u2010derived SDF\u20101 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration. Nat Cell Biol 17: 123\u2013136","journal-title":"Nat Cell Biol"},{"key":"BFEMBJ2020105242_CR50","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature17040","volume":"529","author":"S Rafii","year":"2016","unstructured":"Rafii S, Butler JM, Ding B\u2010S (2016) Angiocrine functions of organ\u2010specific endothelial cells. Nature 529: 316\u2013325","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR51","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature13146","volume":"507","author":"SK Ramasamy","year":"2014","unstructured":"Ramasamy SK, Kusumbe AP, Wang L, Adams RH (2014) Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507: 376\u2013380","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR52","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1146\/annurev-cellbio-111315-124936","volume":"32","author":"SK Ramasamy","year":"2016","unstructured":"Ramasamy SK, Kusumbe AP, Itkin T, Gur\u2010Cohen S, Lapidot T, Adams RH (2016) Regulation of hematopoiesis and osteogenesis by blood vessel\u2013derived signals. Annu Rev Cell Dev Biol 32: 649\u2013675","journal-title":"Annu Rev Cell Dev Biol"},{"key":"BFEMBJ2020105242_CR53","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.2337\/db08-1198","volume":"58","author":"MM Rankin","year":"2009","unstructured":"Rankin MM, Kushner JA (2009) Adaptive \u03b2\u2010cell proliferation is severely restricted with advanced age. Diabetes 58: 1365\u20131372","journal-title":"Diabetes"},{"key":"BFEMBJ2020105242_CR54","first-page":"24","volume":"3","author":"LC Rodrigues","year":"2010","unstructured":"Rodrigues LC, Sinhorini IL, Avanzo JL, Oloris SC, Carneiro CS, Lima CE, Fukumasu H, Costa\u2010Pinto FA, Dagli ML (2010) Diminished angiogenesis in the cornea of mice with heterologous deletion of Connexin 43 gene (Gja1). Braz J Vet Pathol 3: 24\u201330","journal-title":"Braz J Vet Pathol"},{"key":"BFEMBJ2020105242_CR55","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/s41556-019-0304-7","volume":"21","author":"SG Romeo","year":"2019","unstructured":"Romeo SG, Alawi KM, Rodrigues J, Singh A, Kusumbe AP, Ramasamy SK (2019) Endothelial proteolytic activity and interaction with non\u2010resorbing osteoclasts mediate bone elongation. Nat Cell Biol 21: 430\u2013441","journal-title":"Nat Cell Biol"},{"key":"BFEMBJ2020105242_CR56","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41574-019-0228-0","volume":"15","author":"G Russell","year":"2019","unstructured":"Russell G, Lightman S (2019) The human stress response. Nat Rev Endocrinol 15: 525\u2013534","journal-title":"Nat Rev Endocrinol"},{"key":"BFEMBJ2020105242_CR57","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/ni.2017","volume":"12","author":"A Schajnovitz","year":"2011","unstructured":"Schajnovitz A, Itkin T, D'Uva G, Kalinkovich A, Golan K, Ludin A, Cohen D, Shulman Z, Avigdor A, Nagler A et al (2011) CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin\u201043 and connexin\u201045 gap junctions. Nat Immunol 12: 391\u2013398","journal-title":"Nat Immunol"},{"key":"BFEMBJ2020105242_CR58","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrm.2016.87","volume":"17","author":"M Simons","year":"2016","unstructured":"Simons M, Gordon E, Claesson\u2010Welsh L (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 17: 611\u2013625","journal-title":"Nat Rev Mol Cell Biol"},{"key":"BFEMBJ2020105242_CR59","first-page":"1","volume":"4","author":"A Singh","year":"2019","unstructured":"Singh A, Veeriah V, Xi P, Labella R, Chen J, Romeo SG, Ramasamy SK, Kusumbe AP (2019) Angiocrine signals regulate quiescence and therapy resistance in bone metastasis. JCI insight 4: 1\u201316","journal-title":"JCI insight"},{"key":"BFEMBJ2020105242_CR60","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1016\/S1470-2045(08)70281-X","volume":"9","author":"ER Smith","year":"2008","unstructured":"Smith ER, Xu X\u2010X (2008) Ovarian ageing, follicle depletion, and cancer: a hypothesis for the aetiology of epithelial ovarian cancer involving follicle depletion. Lancet Oncol 9: 1108\u20131111","journal-title":"Lancet Oncol"},{"key":"BFEMBJ2020105242_CR61","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1038\/nprot.2011.365","volume":"6","author":"HJ Snippert","year":"2011","unstructured":"Snippert HJ, Schepers AG, Delconte G, Siersema PD, Clevers H (2011) Slide preparation for single\u2010cell\u2013resolution imaging of fluorescent proteins in their three\u2010dimensional near\u2010native environment. Nat Protoc 6: 1221\u20131228","journal-title":"Nat Protoc"},{"key":"BFEMBJ2020105242_CR62","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1042\/BJ20082319","volume":"419","author":"JL Solan","year":"2009","unstructured":"Solan JL, Lampe PD (2009) Connexin43 phosphorylation: structural changes and biological effects. Biochem J 419: 261\u2013272","journal-title":"Biochem J"},{"key":"BFEMBJ2020105242_CR63","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nature07083","volume":"454","author":"T Tammela","year":"2008","unstructured":"Tammela T, Zarkada G, Wallgard E, Murtom\u00e4ki A, Suchting S, Wirzenius M, Waltari M, Hellstr\u00f6m M, Schomber T, Peltonen R (2008) Blocking VEGFR\u20103 suppresses angiogenic sprouting and vascular network formation. Nature 454: 656\u2013660","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR64","doi-asserted-by":"crossref","first-page":"6382","DOI":"10.1182\/blood-2011-12-399659","volume":"119","author":"Y Tashiro","year":"2012","unstructured":"Tashiro Y, Nishida C, Sato\u2010Kusubata K, Ohki\u2010Koizumi M, Ishihara M, Sato A, Gritli I, Komiyama H, Sato Y, Dan T (2012) Inhibition of PAI\u20101 induces neutrophil\u2010driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice. Blood 119: 6382\u20136393","journal-title":"Blood"},{"key":"BFEMBJ2020105242_CR65","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1530\/JOE-16-0051","volume":"230","author":"AH Tsang","year":"2016","unstructured":"Tsang AH, Astiz M, Friedrichs M, Oster H (2016) Endocrine regulation of circadian physiology. J Endocrinol 230: R1\u2013R11","journal-title":"J Endocrinol"},{"key":"BFEMBJ2020105242_CR66","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.2337\/db08-1651","volume":"58","author":"S\u2010I Tschen","year":"2009","unstructured":"Tschen S\u2010I, Dhawan S, Gurlo T, Bhushan A (2009) Age\u2010dependent decline in \u03b2\u2010cell proliferation restricts the capacity of \u03b2\u2010cell regeneration in mice. Diabetes 58: 1312\u20131320","journal-title":"Diabetes"},{"key":"BFEMBJ2020105242_CR67","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/nrendo.2013.38","volume":"9","author":"JD Veldhuis","year":"2013","unstructured":"Veldhuis JD (2013) Changes in pituitary function with ageing and implications for patient care. Nat Rev Endocrinol 9: 205","journal-title":"Nat Rev Endocrinol"},{"key":"BFEMBJ2020105242_CR68","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/nrd4231","volume":"13","author":"A Vetere","year":"2014","unstructured":"Vetere A, Choudhary A, Burns SM, Wagner BK (2014) Targeting the pancreatic \u03b2\u2010cell to treat diabetes. Nat Rev Drug Discovery 13: 278\u2013289","journal-title":"Nat Rev Drug Discovery"},{"key":"BFEMBJ2020105242_CR69","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nrendo.2013.29","volume":"9","author":"G Vitale","year":"2013","unstructured":"Vitale G, Salvioli S, Franceschi C (2013) Oxidative stress and the ageing endocrine system. Nat Rev Endocrinol 9: 228\u2013240","journal-title":"Nat Rev Endocrinol"},{"key":"BFEMBJ2020105242_CR70","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nature09002","volume":"465","author":"Y Wang","year":"2010","unstructured":"Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, Adams S, Davy A, Deutsch U, L\u00fcthi U (2010) Ephrin\u2010B2 controls VEGF\u2010induced angiogenesis and lymphangiogenesis. Nature 465: 483\u2013486","journal-title":"Nature"},{"key":"BFEMBJ2020105242_CR71","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.immuni.2018.03.024","volume":"48","author":"Q Wei","year":"2018","unstructured":"Wei Q, Frenette PS (2018) Niches for hematopoietic stem cells and their progeny. Immunity 48: 632\u2013648","journal-title":"Immunity"},{"key":"BFEMBJ2020105242_CR72","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1095\/biolreprod.113.111690","volume":"89","author":"E Winterhager","year":"2013","unstructured":"Winterhager E, Gellhaus A, Blois SM, Hill LA, Barr KJ, Kidder GM (2013) Decidual angiogenesis and placental orientation are altered in mice heterozygous for a dominant loss\u2010of\u2010function Gja1 (connexin43) mutation. Biol Reprod 89: 111","journal-title":"Biol Reprod"},{"key":"BFEMBJ2020105242_CR73","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.devcel.2009.05.009","volume":"17","author":"ESM Wong","year":"2009","unstructured":"Wong ESM, Le Guezennec X, Demidov ON, Marshall NT, Wang ST, Krishnamurthy J, Sharpless NE, Dunn NR, Bulavin DV (2009) p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age. Dev Cell 17: 142\u2013149","journal-title":"Dev Cell"},{"key":"BFEMBJ2020105242_CR74","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.maturitas.2009.10.018","volume":"65","author":"K Wylie","year":"2010","unstructured":"Wylie K, Kenney G (2010) Sexual dysfunction and the ageing male. Maturitas 65: 23\u201327","journal-title":"Maturitas"},{"key":"BFEMBJ2020105242_CR75","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.2337\/db07-0291","volume":"56","author":"T Yano","year":"2007","unstructured":"Yano T, Liu Z, Donovan J, Thomas MK, Habener JF (2007) Stromal cell\u2010derived factor\u20101 (SDF\u20101)\/CXCL12 attenuates diabetes in mice and promotes pancreatic \u03b2\u2010cell survival by activation of the prosurvival kinase Akt. Diabetes 56: 2946\u20132957","journal-title":"Diabetes"},{"key":"BFEMBJ2020105242_CR76","first-page":"883","volume":"23","author":"P Yesil","year":"2008","unstructured":"Yesil P, Lammert E (2008) Islet dynamics, a glimpse at beta cell proliferation. Histol Histopathol 23: 883\u2013895","journal-title":"Histol Histopathol"},{"key":"BFEMBJ2020105242_CR77","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s13046-019-1156-5","volume":"38","author":"Q Zhang","year":"2019","unstructured":"Zhang Q, Lu S, Li T, Yu L, Zhang Y, Zeng H, Qian X, Bi J, Lin Y (2019) ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa\/VEGFR2\/ERK pathway. J Exp Clin Cancer Res 38: 173","journal-title":"J Exp Clin Cancer Res"},{"key":"BFEMBJ2020105242_CR78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/(SICI)1098-2353(1996)9:1<1::AID-CA1>3.0.CO;2-M","volume":"9","author":"ZG Zhou","year":"1996","unstructured":"Zhou ZG, Gao XH, Wayand WU, Xiao LJ, Du Y (1996) Pancreatic microcirculation in the monkey with special reference to the blood drainage system of Langerhans islets: light and scanning electron microscopic study. Clin Anat 9: 1\u20139","journal-title":"Clin Anat"}],"container-title":["The EMBO Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.15252\/embj.2020105242.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.15252\/embj.2020105242","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.15252\/embj.2020105242\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.embopress.org\/doi\/pdf\/10.15252\/embj.2020105242","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.15252\/embj.2020105242.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T20:12:08Z","timestamp":1779307928000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.15252\/embj.2020105242"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,20]]},"references-count":78,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1,4]]}},"alternative-id":["BFEMBJ2020105242"],"URL":"https:\/\/doi.org\/10.15252\/embj.2020105242","relation":{},"ISSN":["0261-4189","1460-2075"],"issn-type":[{"value":"0261-4189","type":"print"},{"value":"1460-2075","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,20]]},"assertion":[{"value":"9 April 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 September 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 September 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"EMBJ2020105242"}}