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Gold standard anti-vascular endothelial growth factor (VEGF) treatment is an effective therapy, but the long-term prevention of visual decline has not been as successful. This warrants the need to elucidate potential VEGF-independent pathways. We generated blood out-growth endothelial cells (BOECs) from wet AMD and normal control subjects, then induced angiogenic sprouting of BOECs using a fibrin gel bead assay. To deconvolute endothelial heterogeneity, we performed single-cell transcriptomic analysis on the sprouting BOECs, revealing a spectrum of cell states. Our wet AMD BOECs share common pathways with choroidal neovascularization such as extracellular matrix remodeling that promoted proangiogenic phenotype, and our \u2018activated\u2019 BOEC subpopulation demonstrated proinflammatory hallmarks, resembling the tip-like cells in vivo. We uncovered new molecular insights that pathological angiogenesis in wet AMD BOECs could also be driven by interleukin signaling and amino acid metabolism. A web-based visualization of the sprouting BOEC single-cell transcriptome has been created to facilitate further discovery research.<\/jats:p>","DOI":"10.3390\/ijms232012549","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T20:32:23Z","timestamp":1666211543000},"page":"12549","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Single-Cell Transcriptome of Wet AMD Patient-Derived Endothelial Cells in Angiogenic Sprouting"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1158-1432","authenticated-orcid":false,"given":"Natalie Jia Ying","family":"Yeo","sequence":"first","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Wazny","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nhi Le Uyen","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Yi","family":"Ng","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan Xing","family":"Wu","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao","family":"Fan","sequence":"additional","affiliation":[{"name":"Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore"},{"name":"Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore 169857, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3358-3516","authenticated-orcid":false,"given":"Chui Ming Gemmy","family":"Cheung","sequence":"additional","affiliation":[{"name":"Duke-NUS Medical School, National University of Singapore, Singapore 169857, Singapore"},{"name":"Singapore Eye Research Institute, Singapore 169856, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7127-9107","authenticated-orcid":false,"given":"Christine","family":"Cheung","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921, Singapore"},{"name":"Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1136\/bjophthalmol-2011-300539","article-title":"Global estimates of visual impairment: 2010","volume":"96","author":"Pascolini","year":"2012","journal-title":"Br. J. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob. Health"},{"key":"ref_3","unstructured":"Nguyen, Q.D., Rodrigues, E.B., Farah, M.E., and Mieler, W.F. (2010). CHAPTER 18-Neovascular age-related macular degeneration. Retinal Pharmacotherapy, W.B. Saunders."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.stem.2016.12.015","article-title":"Nicotinamide ameliorates disease phenotypes in a human iPSC model of age-related macular degeneration","volume":"20","author":"Saini","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/eye.2016.216","article-title":"Structural and molecular changes in the aging choroid: Implications for age-related macular degeneration","volume":"31","author":"Chirco","year":"2017","journal-title":"Eye"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.neuron.2012.06.018","article-title":"Mechanisms of age-related macular degeneration","volume":"75","author":"Ambati","year":"2012","journal-title":"Neuron"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.mam.2012.04.005","article-title":"Understanding age-related macular degeneration (AMD): Relationships between the photoreceptor\/retinal pigment epithelium\/Bruch\u2019s membrane\/choriocapillaris complex","volume":"33","author":"Bhutto","year":"2012","journal-title":"Mol. Asp. Med."},{"key":"ref_8","first-page":"510285","article-title":"Current Treatment Limitations in Age-Related Macular Degeneration and Future Approaches Based on Cell Therapy and Tissue Engineering","volume":"2014","author":"Sancho","year":"2014","journal-title":"J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/eye.2015.251","article-title":"Photodynamic therapy: Current role in the treatment of chorioretinal conditions","volume":"30","author":"Newman","year":"2016","journal-title":"Eye"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1080\/17460441.2018.1430136","article-title":"Models of retinal diseases and their applicability in drug discovery","volume":"13","author":"Malek","year":"2018","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1016\/j.ophtha.2013.03.046","article-title":"Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: A multicenter cohort study (SEVEN-UP)","volume":"120","author":"Rofagha","year":"2013","journal-title":"Ophthalmology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1136\/bjophthalmol-2013-303513","article-title":"Non-responders to treatment with antagonists of vascular endothelial growth factor in age-related macular degeneration","volume":"97","author":"Krebs","year":"2013","journal-title":"Br. J. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.mam.2012.06.003","article-title":"Animal models of age related macular degeneration","volume":"33","author":"Pennesi","year":"2012","journal-title":"Mol. Asp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1002\/jcp.10246","article-title":"VEGF-TRAPR1R2 suppresses choroidal neovascularization and VEGF-induced breakdown of the blood\u2013retinal barrier","volume":"195","author":"Saishin","year":"2003","journal-title":"J. Cell. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4738","DOI":"10.1167\/iovs.09-4890","article-title":"Relative contribution of VEGF and TNF-\u03b1 in the cynomolgus laser-induced CNV model: Comparing the efficacy of bevacizumab, adalimumab, and ESBA105","volume":"51","author":"Lichtlen","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Volland, S., Esteve-Rudd, J., Hoo, J., Yee, C., and Williams, D.S. (2015). A comparison of some organizational characteristics of the mouse central retina and the human macula. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125631"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.tig.2007.03.001","article-title":"The challenge of modeling macular degeneration in mice","volume":"23","author":"Marmorstein","year":"2007","journal-title":"Trends Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1038\/nprot.2013.135","article-title":"Laser-induced choroidal neovascularization model to study age-related macular degeneration in mice","volume":"8","author":"Lambert","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18277","DOI":"10.1073\/pnas.1109703108","article-title":"Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration","volume":"108","author":"Johnson","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"51","DOI":"10.18632\/aging.100516","article-title":"Chronic oxidative stress upregulates Drusen-related protein expression in adult human RPE stem cell-derived RPE cells: A novel culture model for dry AMD","volume":"5","author":"Rabin","year":"2013","journal-title":"Aging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E8214","DOI":"10.1073\/pnas.1710430114","article-title":"Drusen in patient-derived hiPSC-RPE models of macular dystrophies","volume":"114","author":"Galloway","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/978-1-4614-3209-8_36","article-title":"Is age-related macular degeneration a microvascular disease?","volume":"801","author":"Mullins","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1001\/archopht.121.10.1392","article-title":"Polypoidal choroidal vasculopathy: Incidence, demographic features, and clinical characteristics","volume":"121","author":"Sho","year":"2003","journal-title":"Arch. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1136\/bjo.86.10.1093","article-title":"Clinicopathological correlation of polypoidal choroidal vasculopathy revealed by ultrastructural study","volume":"86","author":"Okubo","year":"2002","journal-title":"Br. J. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1136\/bjo.2004.049296","article-title":"The origins of polypoidal choroidal vasculopathy","volume":"89","author":"Yuzawa","year":"2005","journal-title":"Br. J. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Fei, P., Zaitoun, I., Farnoodian, M., Fisk, D.L., Wang, S., Sorenson, C.M., and Sheibani, N. (2014). Expression of thrombospondin-1 modulates the angioinflammatory phenotype of choroidal endothelial cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0116423"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.exer.2005.08.021","article-title":"Choroidal endothelial cells transmigrate across the retinal pigment epithelium but do not proliferate in response to soluble vascular endothelial growth factor","volume":"82","author":"Geisen","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_28","first-page":"189","article-title":"Regulation of signaling events involved in the pathophysiology of neovascular AMD","volume":"22","author":"Wang","year":"2016","journal-title":"Mol. Vis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1002\/sctm.16-0399","article-title":"Connective Tissue Growth Factor Promotes Efficient Generation of Human Induced Pluripotent Stem Cell-Derived Choroidal Endothelium","volume":"6","author":"Songstad","year":"2017","journal-title":"STEM CELLS Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.mvr.2018.12.002","article-title":"Generation of an immortalized human choroid endothelial cell line (iChEC-1) using an endothelial cell specific promoter","volume":"123","author":"Giacalone","year":"2019","journal-title":"Microvasc. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wu, K.X., Yeo, N.J.Y., Ng, C.Y., Chioh, F.W.J., Fan, Q., Tian, X., Yang, B., Narayanan, G., Tay, H.M., and Hou, H.W. (2022). Hyaluronidase-1-mediated glycocalyx impairment underlies endothelial abnormalities in polypoidal choroidal vasculopathy. BMC Biol., 20.","DOI":"10.1186\/s12915-022-01244-z"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e54271","DOI":"10.15252\/embr.202154271","article-title":"Endothelial-immune crosstalk contributes to vasculopathy in nonalcoholic fatty liver disease","volume":"23","author":"Ng","year":"2022","journal-title":"EMBO Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3872","DOI":"10.1182\/blood-2007-06-097188","article-title":"Genetic endothelial systems biology of sickle stroke risk","volume":"111","author":"Wei","year":"2008","journal-title":"Blood"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ecklu-Mensah, G., Olsen, R.W., Bengtsson, A., Ofori, M.F., Hviid, L., Jensen, A.T.R., and Adams, Y. (2018). Blood outgrowth endothelial cells (BOECs) as a novel tool for studying adhesion of Plasmodium falciparum-infected erythrocytes. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0204177"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wei, P., Milbauer, L.C., Enenstein, J., Nguyen, J., Pan, W., and Hebbel, R.P. (2011). Differential endothelial cell gene expression by African Americans versus Caucasian Americans: A possible contribution to health disparity in vascular disease and cancer. BMC Med., 9.","DOI":"10.1186\/1741-7015-9-2"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.cell.2009.03.025","article-title":"The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis","volume":"137","author":"Benedito","year":"2009","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1083\/jcb.200302047","article-title":"VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia","volume":"161","author":"Gerhardt","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.ceb.2010.08.010","article-title":"Dynamics of endothelial cell behavior in sprouting angiogenesis","volume":"22","author":"Eilken","year":"2010","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1038\/ncb2103","article-title":"Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting","volume":"12","author":"Jakobsson","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/ncb2926","article-title":"The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis","volume":"16","author":"Bentley","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"ref_41","unstructured":"Makowski, G.S. (2014). Chapter One-Matrix Metalloproteinases in Coronary Artery Disease. Advances in Clinical Chemistry, Elsevier."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.cardiores.2005.09.019","article-title":"Involvement of COX-2 in VEGF-induced angiogenesis via P38 and JNK pathways in vascular endothelial cells","volume":"69","author":"Wu","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1053\/j.seminoncol.2004.03.040","article-title":"Multiple roles of COX-2 in tumor angiogenesis: A target for antiangiogenic therapy","volume":"31","author":"Gately","year":"2004","journal-title":"Semin. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S0022-2143(98)90131-7","article-title":"Hypoxia increases thrombospondin-1 transcript and protein in cultured endothelial cells","volume":"132","author":"Phelan","year":"1998","journal-title":"J. Lab. Clin. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1093\/cvr\/cvv243","article-title":"HIF-2\u03b1-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction","volume":"109","author":"Rogers","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1016\/S0002-9440(10)64807-9","article-title":"Endothelin-1 induces an angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo","volume":"157","author":"Salani","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1093\/eurheartj\/ehz305","article-title":"Single-cell transcriptome analyses reveal novel targets modulating cardiac neovascularization by resident endothelial cells following myocardial infarction","volume":"40","author":"Li","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1093\/hmg\/ddi220","article-title":"The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein","volume":"14","author":"Kouprina","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1107\/S0907444908008561","article-title":"Structure of human alpha-enolase (hENO1), a multifunctional glycolytic enzyme","volume":"64","author":"Kang","year":"2008","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1016\/j.bbadis.2009.09.012","article-title":"Triosephosphate isomerase deficiency: New insights into an enigmatic disease","volume":"1792","author":"Orosz","year":"2009","journal-title":"Biochim. Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/j.tem.2020.05.009","article-title":"Metabolic Signatures of Distinct Endothelial Phenotypes","volume":"31","author":"Dumas","year":"2020","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10414","DOI":"10.1038\/s41598-019-46503-2","article-title":"Endothelial tip cells in vitro are less glycolytic and have a more flexible response to metabolic stress than non-tip cells","volume":"9","author":"Vogels","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1002\/stem.1113","article-title":"A Putative Role for the Immunoproteasome in the Maintenance of Pluripotency in Human Embryonic Stem Cells","volume":"30","author":"Atkinson","year":"2012","journal-title":"STEM CELLS"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/sj.onc.1208017","article-title":"Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells","volume":"24","author":"Engelbert","year":"2005","journal-title":"Oncogene"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"18868","DOI":"10.1073\/pnas.1012362107","article-title":"Anaphase-promoting complex\/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes","volume":"107","author":"Colombo","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1073\/pnas.0913668107","article-title":"E3 ubiquitin ligase APC\/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation","volume":"107","author":"Almeida","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5308","DOI":"10.1093\/nar\/gki836","article-title":"NF-kappaB controls the global pro-inflammatory response in endothelial cells: Evidence for the regulation of a pro-atherogenic program","volume":"33","author":"Kempe","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4997","DOI":"10.1182\/blood-2007-08-108597","article-title":"TNF primes endothelial cells for angiogenic sprouting by inducing a tip cell phenotype","volume":"111","author":"Sainson","year":"2008","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1111\/j.1750-3639.2005.tb00117.x","article-title":"The Role of the Extracellular Matrix in Angiogenesis in Malignant Glioma Tumors","volume":"15","author":"Wang","year":"2005","journal-title":"Brain Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/S0002-9440(10)64363-5","article-title":"The alpha(1)beta(1) and alpha(2)beta(1) integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis","volume":"160","author":"Senger","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1126\/science.270.5241.1500","article-title":"Definition of Two Angiogenic Pathways by Distinct \u03b1v Integrins","volume":"270","author":"Friedlander","year":"1995","journal-title":"Science"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/nm0102-27","article-title":"Enhanced pathological angiogenesis in mice lacking \u03b23 integrin or \u03b23 and \u03b25 integrins","volume":"8","author":"Reynolds","year":"2002","journal-title":"Nat. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1007\/s00417-014-2738-8","article-title":"Serum cytokines as biomarkers for age-related macular degeneration","volume":"253","author":"Nassar","year":"2015","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_64","first-page":"535","article-title":"Interleukin-13 and age-related macular degeneration","volume":"10","author":"Fu","year":"2017","journal-title":"Int. J. Ophthalmol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e54257","DOI":"10.7554\/eLife.54257","article-title":"Role of IL-4 in bone marrow driven dysregulated angiogenesis and age-related macular degeneration","volume":"9","author":"Baba","year":"2020","journal-title":"eLife"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.4049\/jimmunol.165.5.2818","article-title":"The Activity of Soluble VCAM-1 in Angiogenesis Stimulated by IL-4 and IL-13","volume":"165","author":"Fukushi","year":"2000","journal-title":"J. Immunol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrm.2016.87","article-title":"Mechanisms and regulation of endothelial VEGF receptor signalling","volume":"17","author":"Simons","year":"2016","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.yexcr.2005.10.028","article-title":"Eph receptor and ephrin ligand-mediated interactions during angiogenesis and tumor progression","volume":"312","author":"Schaffner","year":"2006","journal-title":"Exp. Cell Res."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Vreeken, D., Zhang, H., van Zonneveld, A.J., and van Gils, J.M. (2020). Ephs and Ephrins in Adult Endothelial Biology. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165623"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.cellsig.2016.10.003","article-title":"Regulation of endothelial migration and proliferation by ephrin-A1","volume":"29","author":"Wiedemann","year":"2017","journal-title":"Cell Signal"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.cell.2018.03.001","article-title":"Amino Acid Restriction Triggers Angiogenesis via GCN2\/ATF4 Regulation of VEGF and H(2)S Production","volume":"173","author":"Longchamp","year":"2018","journal-title":"Cell"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.vph.2018.11.001","article-title":"Role of amino acid metabolism in angiogenesis","volume":"112","author":"Oberkersch","year":"2019","journal-title":"Vasc. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.cmet.2020.03.009","article-title":"Single-Cell RNA Sequencing Maps Endothelial Metabolic Plasticity in Pathological Angiogenesis","volume":"31","author":"Rohlenova","year":"2020","journal-title":"Cell Metab."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"38913","DOI":"10.1074\/jbc.M112.388389","article-title":"The TG-interacting factor TGIF1 regulates stress-induced proinflammatory phenotype of endothelial cells","volume":"287","author":"Hneino","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0092-8674(00)81848-6","article-title":"Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth","volume":"88","author":"Boehm","year":"1997","journal-title":"Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.matbio.2010.11.001","article-title":"The multiple functions of collagen XVIII in development and disease","volume":"30","author":"Seppinen","year":"2011","journal-title":"Matrix Biol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S0002-9440(10)62246-8","article-title":"Endostatin Overexpression Specifically in the Lens and Skin Leads to Cataract and Ultrastructural Alterations in Basement Membranes","volume":"166","author":"Elamaa","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Edgar, L.T., Underwood, C.J., Guilkey, J.E., Hoying, J.B., and Weiss, J.A. (2014). Extracellular Matrix Density Regulates the Rate of Neovessel Growth and Branching in Sprouting Angiogenesis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0085178"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1161\/01.RES.0000191547.64391.e3","article-title":"Endothelial Extracellular Matrix","volume":"97","author":"Davis","year":"2005","journal-title":"Circ. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1161\/01.ATV.0000209501.56852.6c","article-title":"Dynamics and plasticity of Weibel-Palade bodies in endothelial cells","volume":"26","author":"Rondaij","year":"2006","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1038\/s41598-018-19473-0","article-title":"Intravitreal injection of aflibercept, an anti-VEGF antagonist, down-regulates plasma von Willebrand factor in patients with age-related macular degeneration","volume":"8","author":"Yamashita","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/S0161-6420(00)00663-1","article-title":"Age-related macular degeneration is associated with increased vascular endothelial growth factor, hemorheology and endothelial dysfunction","volume":"108","author":"Lip","year":"2001","journal-title":"Ophthalmology"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1182\/blood-2005-12-007484","article-title":"VEGF regulates the mobilization of VEGFR2\/KDR from an intracellular endothelial storage compartment","volume":"108","author":"Gampel","year":"2006","journal-title":"Blood"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.7150\/ijbs.49890","article-title":"The Role of Inflammation in Age-Related Macular Degeneration","volume":"16","author":"Tan","year":"2020","journal-title":"Int. J. Biol. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1126\/science.1110189","article-title":"Complement Factor H Polymorphism and Age-Related Macular Degeneration","volume":"308","author":"Edwards","year":"2005","journal-title":"Science"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"165956","DOI":"10.1016\/j.bbadis.2020.165956","article-title":"Transcriptome analysis provides new molecular signatures in sporadic Cerebral Cavernous Malformation endothelial cells","volume":"1866","author":"Scimone","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"146","DOI":"10.3389\/fgene.2020.00146","article-title":"High-Throughput Sequencing to Detect Novel Likely Gene-Disrupting Variants in Pathogenesis of Sporadic Brain Arteriovenous Malformations","volume":"11","author":"Scimone","year":"2020","journal-title":"Front. Genet."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s10072-018-3674-x","article-title":"Vis-\u00e0-vis: A focus on genetic features of cerebral cavernous malformations and brain arteriovenous malformations pathogenesis","volume":"40","author":"Scimone","year":"2019","journal-title":"Neurol. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3389\/fphys.2014.00114","article-title":"The role IL-1 in tumor-mediated angiogenesis","volume":"5","author":"Voronov","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1038\/s41598-019-39018-3","article-title":"Interleukin-13 receptor \u03b12 is a novel marker and potential therapeutic target for human melanoma","volume":"9","author":"Okamoto","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Geindreau, M., Bruchard, M., and Vegran, F. (2022). Role of Cytokines and Chemokines in Angiogenesis in a Tumor Context. Cancers, 14.","DOI":"10.3390\/cancers14102446"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"295","DOI":"10.3389\/fmed.2018.00295","article-title":"Recent Advances in Endothelial Colony Forming Cells Toward Their Use in Clinical Translation","volume":"5","author":"Paschalaki","year":"2018","journal-title":"Front. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1002\/stem.1488","article-title":"Dysfunction of Endothelial Progenitor Cells from Smokers and Chronic Obstructive Pulmonary Disease Patients Due to Increased DNA Damage and Senescence","volume":"31","author":"Paschalaki","year":"2013","journal-title":"Stem Cells"},{"key":"ref_94","first-page":"e53384","article-title":"Generation and Culture of Blood Outgrowth Endothelial Cells from Human Peripheral Blood","volume":"106","author":"Ormiston","year":"2015","journal-title":"J. Vis. Exp."},{"key":"ref_95","first-page":"e186","article-title":"Optimized fibrin gel bead assay for the study of angiogenesis","volume":"29","author":"Nakatsu","year":"2007","journal-title":"J. Vis. Exp."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.cels.2019.03.003","article-title":"DoubletFinder: Doublet Detection in Single-Cell RNA Sequencing Data Using Artificial Nearest Neighbors","volume":"8","author":"McGinnis","year":"2019","journal-title":"Cell Syst."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2748","DOI":"10.1016\/j.celrep.2019.04.102","article-title":"Single-Cell Transcriptional Profiling of Aortic Endothelium Identifies a Hierarchy from Endovascular Progenitors to Differentiated Cells","volume":"27","author":"Lukowski","year":"2019","journal-title":"Cell Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"giy083","DOI":"10.1093\/gigascience\/giy083","article-title":"Clustering trees: A visualization for evaluating clusterings at multiple resolutions","volume":"7","author":"Zappia","year":"2018","journal-title":"GigaScience"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1039\/C5MB00663E","article-title":"ReactomePA: An R\/Bioconductor package for reactome pathway analysis and visualization","volume":"12","author":"Yu","year":"2016","journal-title":"Mol. BioSyst."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12549\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:57:26Z","timestamp":1760144246000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/20\/12549"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,19]]},"references-count":102,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["ijms232012549"],"URL":"https:\/\/doi.org\/10.3390\/ijms232012549","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,19]]}}}