{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T03:34:38Z","timestamp":1779161678864,"version":"3.51.4"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,4]],"date-time":"2021-09-04T00:00:00Z","timestamp":1630713600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003329","name":"Ministerio de Econom\u00eda y Competitividad","doi-asserted-by":"publisher","award":["SAF2017-83351R"],"award-info":[{"award-number":["SAF2017-83351R"]}],"id":[{"id":"10.13039\/501100003329","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Von Hippel\u2013Lindau disease (VHL) is a rare hereditary disease characterized by the predisposal to develop different types of highly vascularized tumors. VHL patients carry a VHL mutation that causes partial lack of functional VHL protein (pVHL) in all cells, and a total lack thereof in cells harboring a second hit mutation. Absence of pVHL generates a prolonged state of pseudo-hypoxia in the cell due to accumulation of hypoxia inducible factor, an important transcription factor regulating pro-tumorigenic genes. The work here presented focuses on characterizing the endothelium of VHL patients, by means of blood outgrowth endothelial cells (BOECs). Transcriptome analysis of VHL-derived BOECs, further supported by in vitro assays, shows that these cells are at a disadvantage, as evidenced by loss of cell adhesion capacity, angiogenesis defects, and immune response and oxidative metabolic gene downregulation, which induce oxidative stress. These results suggest that the endothelium of VHL patients is functionally compromised and more susceptible to tumor development. These findings contribute to shedding light on the vascular landscape of VHL patients preceding the second hit mutation in the VHL gene. This knowledge could be useful in searching for new therapies for these patients and other vascular diseases.<\/jats:p>","DOI":"10.3390\/cells10092313","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T10:59:12Z","timestamp":1630925952000},"page":"2313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The Endothelial Landscape and Its Role in Von Hippel\u2013Lindau Disease"],"prefix":"10.3390","volume":"10","author":[{"given":"Isabel","family":"de Rojas-P","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margaritas Salas, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n del C\u00e1ncer, Instituto de Biolog\u00eda Molecular y Celular del C\u00e1ncer, 37007 Salamanca, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Albi\u00f1ana","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margaritas Salas, 28040 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lyudmyla","family":"Taranets","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine VIII, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Strasse 14, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc\u00eda","family":"Recio-Poveda","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margaritas Salas, 28040 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6596-9600","authenticated-orcid":false,"given":"Angel M.","family":"Cuesta","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margaritas Salas, 28040 Madrid, Spain"},{"name":"Departamento de Bioqu\u00edmica, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikita","family":"Popov","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine VIII, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Strasse 14, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6933-7590","authenticated-orcid":false,"given":"Thales","family":"Kronenberger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine VIII, University Hospital T\u00fcbingen, Otfried-M\u00fcller-Strasse 14, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6310-2245","authenticated-orcid":false,"given":"Luisa M.","family":"Botella","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margaritas Salas, 28040 Madrid, Spain"},{"name":"CIBERER, Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, ISCIII, 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1210\/jc.2009-2245","article-title":"Mutations of the metabolic genes IDH1, IDH2, and SDHAF2 are not major determinants of the pseudohypoxic phenotype of sporadic pheochromocytomas and paragangliomas","volume":"95","author":"Yao","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1038\/ejhg.2010.175","article-title":"Von Hippel-Lindau disease: A clinical and scientific review","volume":"19","author":"Maher","year":"2011","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1093\/hmg\/10.7.763","article-title":"Genotype-phenotype correlation in von Hippel-Lindau syndrome","volume":"10","author":"Friedrich","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20","DOI":"10.15586\/jkcvhl.2017.88","article-title":"A Review of Von Hippel-Lindau Syndrome","volume":"4","author":"Varshney","year":"2017","journal-title":"J. Kidney Cancer VHL"},{"key":"ref_5","first-page":"765","article-title":"Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors","volume":"60","author":"Prowse","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1002\/ajmg.10320","article-title":"Cancer genetics","volume":"111","author":"Knudson","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"43611","DOI":"10.1074\/jbc.M107880200","article-title":"The von Hippel-Lindau Tumor Suppressor Protein Mediates Ubiquitination of Activated Atypical Protein Kinase C","volume":"276","author":"Okuda","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/20459","article-title":"The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis","volume":"399","author":"Maxwell","year":"1999","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/S0092-8674(01)00507-4","article-title":"C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation","volume":"107","author":"Epstein","year":"2001","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16767","DOI":"10.1074\/jbc.M901790200","article-title":"Genome-wide association of hypoxia-inducible factor (HIF)-1\u03b1 and HIF-2\u03b1 DNA binding with expression profiling of hypoxia-inducible transcripts","volume":"284","author":"Mole","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/s41581-019-0182-z","article-title":"Mechanisms of hypoxia signalling: New implications for nephrology","volume":"15","author":"Ratcliffe","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13046-020-1532-1","article-title":"Erratum: Targeting hypoxia in tumor: A new promising therapeutic strategy","volume":"39","author":"Bosco","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1152\/jappl.2000.88.4.1474","article-title":"HIF-1: Mediator of physiological and pathophysiological responses to hypoxia","volume":"88","author":"Semenza","year":"2000","journal-title":"J. Appl. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S0039-6257(01)00245-4","article-title":"Von Hippel-Lindau disease","volume":"46","author":"Singh","year":"2001","journal-title":"Surv. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.semcancer.2012.05.005","article-title":"Von Hippel-Lindau: How a rare disease illuminates cancer biology","volume":"23","author":"Richard","year":"2013","journal-title":"Semin. Cancer Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"210","DOI":"10.3171\/JNS\/2008\/108\/2\/0210","article-title":"Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease","volume":"108","author":"Jagannathan","year":"2008","journal-title":"J. Neurosurg."},{"key":"ref_17","first-page":"29","article-title":"Neurosurgical treatment of von Hippel-Lindau-associated hemangioblastomas: Benefits, risks and outcome","volume":"52","author":"Pavesi","year":"2008","journal-title":"J. Neurosurg. Sci."},{"key":"ref_18","first-page":"975","article-title":"Von Hippel-Lindau Disease (VHL): A need for a murine model with retinal hemangioblastoma","volume":"27","author":"Park","year":"2012","journal-title":"Histol. Histopathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1158\/0008-5472.CAN-17-1718","article-title":"Deletion of the von Hippel-Lindau gene in hemangioblasts causes Hemangioblastoma-like Lesions in Murine Retina","volume":"78","author":"Wang","year":"2018","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1186\/s13023-015-0343-5","article-title":"Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients","volume":"10","author":"Segura","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13023-017-0664-7","article-title":"Repurposing propranolol as a drug for the treatment of retinal haemangioblastomas in von Hippel-Lindau disease","volume":"12","author":"Escribano","year":"2017","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10062","DOI":"10.1038\/s41598-019-46448-6","article-title":"The \u03b22-adrenergic receptor antagonist ICI-118,551 blocks the constitutively activated HIF signalling in hemangioblastomas from von Hippel-Lindau disease","volume":"9","author":"Cuesta","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Albi\u00f1ana, V., Gallardo-Vara, E., de Rojas-P, I., Recio-Poveda, L., Aguado, T., Canto-Cano, A., Aguirre, D.T., Serra, M.M., Gonz\u00e1lez-Peramato, P., and Mart\u00ednez-Pi\u00f1eiro, L. (2020). Targeting \u03b22-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel\u2013Lindau Disease. J. Clin. Med., 9.","DOI":"10.3390\/jcm9092740"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1186\/s13023-020-01410-y","article-title":"CLN5 in heterozygosis may protect against the development of tumors in a VHL patient","volume":"15","author":"Cuesta","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1034\/j.1600-0609.2000.065004215.x","article-title":"Circulating endothelial cells in vascular disorders: New insights into an old concept","volume":"65","author":"Sampol","year":"2000","journal-title":"Eur. J. Haematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1161\/01.ATV.0000073832.49290.B5","article-title":"Endothelial progenitor cells: Mobilization, differentiation, and homing","volume":"23","author":"Hristov","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/s12079-016-0352-8","article-title":"VEGF-A\/VEGFR2 signaling network in endothelial cells relevant to angiogenesis","volume":"10","author":"Abhinand","year":"2016","journal-title":"J. Cell Commun. Signal."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1161\/01.RES.86.12.1198","article-title":"Vascular endothelial growth factor (165) gene transfer augments circulating endothelial progenitor cells in human subjects","volume":"86","author":"Kalka","year":"2000","journal-title":"Circ. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/S0014-5793(01)02520-0","article-title":"Identification of human endomucin-1 and -2 as membrane-bound O-sialoglycoproteins with anti-adhesive activity","volume":"499","author":"Kinoshita","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.7150\/ijbs.7502","article-title":"The vascular endothelium and human diseases","volume":"9","author":"Rajendran","year":"2013","journal-title":"Int. J. Biol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/376517a0","article-title":"Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1","volume":"376","author":"Koch","year":"1995","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/0962-8924(96)84942-7","article-title":"Cell adhesion and angiogenesis","volume":"6","author":"Cheresh","year":"1996","journal-title":"Trends Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/j.stemcr.2017.04.015","article-title":"Cardiosphere-Derived Cells Require Endoglin for Paracrine-Mediated Angiogenesis","volume":"8","author":"Redgrave","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/nri910","article-title":"NF-\u03baB regulation in the immune system","volume":"2","author":"Li","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1172\/JCI11830","article-title":"NF-\u03baB in defense and disease NF-\u03baB: A key role in inflammatory diseases","volume":"107","author":"Tak","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"46230","DOI":"10.1074\/jbc.M305420200","article-title":"Identification of Hypoxia-response Element in the Human Endothelial Nitric-oxide Synthase Gene Promoter","volume":"278","author":"Coulet","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3013","DOI":"10.1128\/MCB.00324-14","article-title":"Hypoxia-Inducible Factor\/MAZ-Dependent Induction of Caveolin-1 Regulates Colon Permeability through Suppression of Occludin, Leading to Hypoxia-Induced Inflammation","volume":"34","author":"Xie","year":"2014","journal-title":"Mol. Cell. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"109524","DOI":"10.1016\/j.cellsig.2020.109524","article-title":"Role of oxygen and the HIF-pathway","volume":"69","author":"Buchholz","year":"2020","journal-title":"Cell. Signal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1089\/ars.2010.3815","article-title":"Transcriptional profile of genes involved in oxidative stress and antioxidant defense in a dietary murine model of steatohepatitis","volume":"15","author":"Gornicka","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"10892","DOI":"10.1074\/jbc.M800102200","article-title":"Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia","volume":"283","author":"Zhang","year":"2008","journal-title":"J. Biol. Chem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2313\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:56:16Z","timestamp":1760165776000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2313"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,4]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["cells10092313"],"URL":"https:\/\/doi.org\/10.3390\/cells10092313","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,4]]}}}