{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T19:44:18Z","timestamp":1792698258271,"version":"4.5.0"},"reference-count":78,"publisher":"Bioscientifica","issue":"4","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Pheochromocytomas in von Hippel\u2013Lindau (VHL) syndrome produce exclusively norepinephrine, whereas those in multiple endocrine neoplasia type 2 (MEN 2) produce epinephrine. This study examined the pathways activated in VHL-associated pheochromocytomas by comparing gene expression profiles in VHL and MEN 2 tumors in relationship to profiles in sporadic norepinephrine- and epinephrine-producing tumors. Larger and more distinct differences in gene expression among hereditary than sporadic tumors indicated the importance of the underlying mutation to gene expression profiles. Many of the genes over-expressed in VHL compared with MEN 2 tumors were clearly linked to the hypoxia-driven angiogenic pathways that are activated in VHL-associated tumorigenesis. Such genes included those for the glucose transporter, vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 2, tie-1, VEGF receptor 2 and its coreceptor, neuropilin-1. Other up-regulated genes, such as connective tissue growth factor, cysteine-rich 61, matrix metalloproteinase 1, vascular endothelial cadherin, tenascin C, stanniocalcin 1, and cyclooxygenases 1 and 2 are known to be involved in VEGF-regulated angiogenesis. Shared differences in expression of subsets of genes in norepinephrine- versus epinephrine-producing hereditary and sporadic pheochromocytomas indicated other differences in gene expression that may underlie the biochemical phenotype. Over-expression of the hypoxia-inducible transcription factor, HIF-2\u03b1, in norepinephrine-predominant sporadic and VHL tumors compared with epinephrine-producing tumors indicates that expression of this gene depends on the noradrenergic biochemical phenotype. The findings fit with the known expression of HIF-2\u03b1 in norepinephrine-producing cells of the sympathetic nervous system and might explain both the development and noradrenergic biochemical phenotype of pheochromocytomas in VHL syndrome.<\/jats:p>","DOI":"10.1677\/erc.1.00838","type":"journal-article","created":{"date-parts":[[2005,1,21]],"date-time":"2005-01-21T16:19:42Z","timestamp":1106324382000},"page":"897-911","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":177,"title":["Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel\u2013Lindau syndrome"],"prefix":"10.1530","volume":"11","author":[{"given":"G","family":"Eisenhofer","sequence":"first","affiliation":[{"name":"Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T-T","family":"Huynh","sequence":"additional","affiliation":[{"name":"Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K","family":"Pacak","sequence":"additional","affiliation":[{"name":"1Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F M","family":"Brouwers","sequence":"additional","affiliation":[{"name":"1Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M M","family":"Walther","sequence":"additional","affiliation":[{"name":"2Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W M","family":"Linehan","sequence":"additional","affiliation":[{"name":"2Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P J","family":"Munson","sequence":"additional","affiliation":[{"name":"3Center for Information Technology, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Mannelli","sequence":"additional","affiliation":[{"name":"4Department of Clinical Pathophysiology, University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D S","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A G","family":"Elkahloun","sequence":"additional","affiliation":[{"name":"5Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"2026070905542778900_ABE-AND-SATO-2001","doi-asserted-by":"crossref","unstructured":"Abe\n            M\n           & Sato Y 2001 cDNA microarray analysis of the gene expression profile of VEGF-activated human umbilical vein endothelial cells. 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