{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Endothelial‐specific molecule 1 (ESM1), also known as endocan, is a secreted dermatan sulfate proteoglycan that is primarily produced by activated endothelial cells in response to proangiogenic and proinflammatory stimuli. Multiple studies have demonstrated that ESM1 is robustly induced by vascular endothelial growth factor (VEGF) and cytokines, thereby acting as both a downstream target and a modulator of VEGF‐dependent signaling. In this context, its expression in endothelial tip cells is associated with enhanced endothelial sprouting, tube formation, and increased vascular permeability, as evidenced by loss‐of‐function studies in retina angiogenesis models and in vitro assays (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in physiological and developmental angiogenesis, ESM1 is markedly overexpressed in the vascular beds of numerous tumors – including lung, bladder, colorectal, hepatocellular, renal, and glioblastoma – where its elevated levels correlate with tumor progression, invasiveness, and poor clinical outcome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": " In addition, inducible expression of ESM1 in lymphatic endothelial cells has been linked to enhanced responses to both VEGF-A and VEGF-C and, consequently, to lymphangiogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n ESM1 is likewise emerging as a biomarker of endothelial dysfunction in a range of inflammatory and cardiovascular conditions. Elevated circulating levels of ESM1 have been detected in patients with essential hypertension, sepsis, acute coronary syndrome, and even in inflammatory CNS disorders such as migraine."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "14"}]}, {"type": "t", "text": " In several cases, serum ESM1 concentrations correlate with classic proangiogenic factors (e.g., VEGF) and with markers of inflammation and endothelial activation, suggesting that it may serve both as a prognostic indicator and as a potential therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "18"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, mechanistic studies have shown that ESM1 can interact with components of the extracellular matrix (e.g., fibronectin) to enhance the bioavailability of VEGF-A165, thereby further potentiating VEGF receptor-2 signaling and promoting endothelial cell migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Its regulation by hypoxia inducible factors such as HIF-1α also implicates ESM1 in the adaptive responses of tumors to hypoxic microenvironments"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", while cross-talk with other signaling cascades (for example, through ICAP1–NOTCH interactions) further underlines the multifaceted role of ESM1 in modulating angiogenic and inflammatory pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, ESM1 functions as a critical mediator of angiogenesis and inflammation by integrating cues from VEGF and inflammatory cytokines to modulate endothelial cell behavior. Its upregulation in pathological conditions – including various cancers and inflammatory vascular disorders – and the impact of its genetic or pharmacologic modulation on endothelial function underscore its potential as both a prognostic biomarker and a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "20"}, {"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Susana F Rocha, Maria Schiller, Ding Jing, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Esm1 modulates endothelial tip cell behavior and vascular permeability by enhancing VEGF bioavailability."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.115.304718"}], "href": "https://doi.org/10.1161/CIRCRESAHA.115.304718"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25057127"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25057127"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Geraldine A Strasser, Joshua S Kaminker, Marc Tessier-Lavigne "}, {"type": "b", "children": [{"type": "t", "text": "Microarray analysis of retinal endothelial tip cells identifies CXCR4 as a mediator of tip cell morphology and branching."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2009-07-230284"}], "href": "https://doi.org/10.1182/blood-2009-07-230284"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20154215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20154215"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mark Aitkenhead, Shur-Jen Wang, Martin N Nakatsu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of endothelial cell genes expressed in an in vitro model of angiogenesis: induction of ESM-1, (beta)ig-h3, and NrCAM."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Microvasc Res (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1006/mvre.2001.2380"}], "href": "https://doi.org/10.1006/mvre.2001.2380"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11866539"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11866539"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Bogdan Dragos Grigoriu, Florence Depontieu, Arnaud Scherpereel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endocan expression and relationship with survival in human non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-06-0185"}], "href": "https://doi.org/10.1158/1078-0432.CCR-06-0185"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16899604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16899604"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Filip Roudnicky, Cedric Poyet, Peter Wild, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endocan is upregulated on tumor vessels in invasive bladder cancer where it mediates VEGF-A-induced angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-12-1855"}], "href": "https://doi.org/10.1158/0008-5472.CAN-12-1855"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23243026"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23243026"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yun Hee Kang, Na Young Ji, Seung Ro Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ESM-1 regulates cell growth and metastatic process through activation of NF-κB in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2012.06.004"}], "href": "https://doi.org/10.1016/j.cellsig.2012.06.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22735811"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22735811"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Claude-Alain Maurage, Estelle Adam, Jean-Francois Minéo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endocan expression and localization in human glioblastomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuropathol Exp Neurol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/NEN.0b013e3181a52a7f"}], "href": "https://doi.org/10.1097/NEN.0b013e3181a52a7f"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19458546"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19458546"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Geng-Wen Huang, Yi-Ming Tao, Xiang Ding "}, {"type": "b", "children": [{"type": "t", "text": "Endocan expression correlated with poor survival in human hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dig Dis Sci (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10620-008-0346-3"}], "href": "https://doi.org/10.1007/s10620-008-0346-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18592377"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18592377"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "L-Y Chen, X Liu, S-L Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Over-expression of the Endocan gene in endothelial cells from hepatocellular carcinoma is associated with angiogenesis and tumour invasion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Int Med Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/147323001003800213"}], "href": "https://doi.org/10.1177/147323001003800213"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20515564"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20515564"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Jay W Shin, Reto Huggenberger, Michael Detmar "}, {"type": "b", "children": [{"type": "t", "text": "Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2008-05-156331"}], "href": "https://doi.org/10.1182/blood-2008-05-156331"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18614759"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18614759"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Sevket Balta, Dimitri P Mikhailidis, Sait Demirkol, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endocan--a novel inflammatory indicator in newly diagnosed patients with hypertension: a pilot study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Angiology (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/0003319713513492"}], "href": "https://doi.org/10.1177/0003319713513492"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24402320"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24402320"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Shivakumar Subbanna, Nagaraja N Nagre, Nagavedi S Umapathy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ethanol exposure induces neonatal neurodegeneration by enhancing CB1R Exon1 histone H4K8 acetylation and up-regulating CB1R function causing neurobehavioral abnormalities in adult mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Neuropsychopharmacol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/ijnp/pyu028"}], "href": "https://doi.org/10.1093/ijnp/pyu028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25609594"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25609594"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Murat Kose, Samim Emet, Timur Selcuk Akpinar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum Endocan Level and the Severity of Coronary Artery Disease: A Pilot Study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Angiology (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1177/0003319714548870"}], "href": "https://doi.org/10.1177/0003319714548870"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25168956"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25168956"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "M Yücel, D Kotan, G Gurol Çiftçi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Serum levels of endocan, claudin-5 and cytokines in migraine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2016)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27010153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27010153"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Md Ruhul Abid, Xianjin Yi, Kiichiro Yano, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Vascular endocan is preferentially expressed in tumor endothelium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Microvasc Res (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.mvr.2006.05.010"}], "href": "https://doi.org/10.1016/j.mvr.2006.05.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16956626"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16956626"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Xavier Leroy, Sebastien Aubert, Laurent Zini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Vascular endocan (ESM-1) is markedly overexpressed in clear cell renal cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Histopathology (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-2559.2009.03458.x"}], "href": "https://doi.org/10.1111/j.1365-2559.2009.03458.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20102396"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20102396"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Joo Heon Kim, Mee Young Park, Chang Nam Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression of endothelial cell-specific molecule-1 regulated by hypoxia inducible factor-1α in human colon carcinoma: impact of ESM-1 on prognosis and its correlation with clinicopathological features."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2012.2012"}], "href": "https://doi.org/10.3892/or.2012.2012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22948784"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22948784"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Ni Liu, Lian-hai Zhang, Hong Du, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of endothelial cell specific molecule-1 (ESM-1) in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Surg Oncol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1245/s10434-010-1037-9"}], "href": "https://doi.org/10.1245/s10434-010-1037-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20383661"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20383661"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "René Brütsch, Sven S Liebler, Joycelyn Wüstehube, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrin cytoplasmic domain-associated protein-1 attenuates sprouting angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.110.217257"}], "href": "https://doi.org/10.1161/CIRCRESAHA.110.217257"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20616313"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20616313"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Wonhwa Lee, Sae-Kwang Ku, Shin-Woo Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endocan elicits severe vascular inflammatory responses in vitro and in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.24485"}], "href": "https://doi.org/10.1002/jcp.24485"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24446198"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24446198"}]}]}]}