{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:13:16Z","timestamp":1791310396636,"version":"4.3.1"},"reference-count":37,"publisher":"National Academy of Sciences","issue":"42","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,10,17]]},"abstract":"<jats:p>\n                    Allosteric regulation of oxygen delivery by RBCs may have significant effects on tumor growth. Indeed, angiogenesis, the formation of new blood vessels, is induced in growing tumors by low oxygen partial pressure. Hypoxia-inducible genes are switched on, among which are the VEGF gene and its receptors. Most important, under hypoxia, hypoxia-inducible factor 1\u03b1 has a significantly prolonged half-life and up-regulates a number of hypoxia genes. Human microvascular endothelial cells (MECs), when subjected\n                    <jats:italic>in vitro<\/jats:italic>\n                    to hypoxia, align to form vessel-like structures as in the angiogenic process. We report here that, when cultured in hypoxic conditions in the presence of human RBCs loaded with a new membrane-permeant allosteric effector of Hb,\n                    <jats:italic>myo<\/jats:italic>\n                    -inositol trispyrophosphate (ITPP), endothelial cells (ECs) do not align, i.e., do not form \u201cvessel\u201d-like structures, because the \u201cloaded\u201d RBCs are capable of releasing under hypoxia more oxygen than their \u201cnormal\u201d counterparts. Levels of VEGF and of hypoxia-inducible factor 1\u03b1, elevated in the human MECs under hypoxia, were dramatically reduced or even suppressed in the presence of the ITPP-loaded RBCs. Treatment of these ECs directly with free ITPP at different concentrations had no effect on their ability to undertake angiogenesis. Incubation with ITPP enhances the capacity of Hb to release bound oxygen, leading to higher oxygen tension in the hypoxic environment, thus inhibiting hypoxia-induced angiogenesis. These observations are suggestive of a potential\n                    <jats:italic>in vivo<\/jats:italic>\n                    role of ITPP-loaded, \u201clow-O\n                    <jats:sub>2<\/jats:sub>\n                    -affinity\u201d RBCs in cancer therapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0607109103","type":"journal-article","created":{"date-parts":[[2006,10,6]],"date-time":"2006-10-06T20:37:37Z","timestamp":1160167057000},"page":"15576-15581","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":47,"title":["Suppression of hypoxia-induced HIF-1\u03b1 and of angiogenesis in endothelial cells by\n                    <i>myo<\/i>\n                    -inositol trispyrophosphate-treated erythrocytes"],"prefix":"10.1073","volume":"103","author":[{"given":"Claudine","family":"Kieda","sequence":"first","affiliation":[{"name":"*Centre de Biophysique Mol\u00e9culaire, Centre National de la Recherche Scientifique, Unit\u00e9 Propre de Recherche 4301, 45045 Orl\u00e9ans, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Greferath","sequence":"additional","affiliation":[{"name":"Oxyplus, Inc., 200 Boston Avenue, Medford, MA 02155; and"},{"name":"Institut de Science et d'Ing\u00e9nierie Supramol\u00e9culaires, Universit\u00e9 Louis Pasteur, 8 All\u00e9e Gaspard Monge, BP 70028, 67083 Strasbourg Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Crola Da Silva","sequence":"additional","affiliation":[{"name":"*Centre de Biophysique Mol\u00e9culaire, Centre National de la Recherche Scientifique, Unit\u00e9 Propre de Recherche 4301, 45045 Orl\u00e9ans, France;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina C.","family":"Fylaktakidou","sequence":"additional","affiliation":[{"name":"Institut de Science et d'Ing\u00e9nierie Supramol\u00e9culaires, Universit\u00e9 Louis Pasteur, 8 All\u00e9e Gaspard Monge, BP 70028, 67083 Strasbourg Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marie","family":"Lehn","sequence":"additional","affiliation":[{"name":"Institut de Science et d'Ing\u00e9nierie Supramol\u00e9culaires, Universit\u00e9 Louis Pasteur, 8 All\u00e9e Gaspard Monge, BP 70028, 67083 Strasbourg Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Nicolau","sequence":"additional","affiliation":[{"name":"Oxyplus, Inc., 200 Boston Avenue, Medford, MA 02155; and"},{"name":"Institut de Science et d'Ing\u00e9nierie Supramol\u00e9culaires, Universit\u00e9 Louis Pasteur, 8 All\u00e9e Gaspard Monge, BP 70028, 67083 Strasbourg Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,10,17]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.18.1.0287"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2432664"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/82.1.4"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(92)93217-B"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81848-6"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2005.10.006"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/0-387-26206-7_5"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-3090"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(91)90033-U"},{"key":"e_1_3_4_10_2","first-page":"4230","volume":"55","author":"Chen C","year":"1995","unstructured":"C Chen, S Parangi, MJ Tolentino, J Folkman Cancer Res 55, 4230\u20134233 (1995).","journal-title":"Cancer Res"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.10.2.267"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04871"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2005.12.003"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R200030200"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.12.5510"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1996.271.4.C1172"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.15.1.551"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-07-2958"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.2005.02045.x"},{"key":"e_1_3_4_20_2","first-page":"81","volume":"16","author":"Chen L","year":"2006","unstructured":"L Chen, F Shibasaki Clin Calcium 16, 81\u201387 (2006).","journal-title":"Clin Calcium"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(01)02126-2"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0074-7696(04)42004-X"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2006.05.011"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1985.58.6.1810"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.19.6894"},{"key":"e_1_3_4_26_2","first-page":"265","volume-title":"Phytic Acid","author":"Nicolau C","year":"1986","unstructured":"C Nicolau, C Ropars, B Teisseire Phytic Acid, ed E Graf (Pilatus, Minneapolis), pp. 265\u2013290 (1986)."},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0968-0896(02)00162-1"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2005.01.064"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1080\/10623320214736"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgh232"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0121"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00518-9"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.01-0944rev"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00001.2004"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400598"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04478"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2006.06.006"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0607109103","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T15:50:20Z","timestamp":1649778620000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0607109103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,10,17]]},"references-count":37,"journal-issue":{"issue":"42","published-print":{"date-parts":[[2006,10,17]]}},"alternative-id":["10.1073\/pnas.0607109103"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0607109103","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1063826.516754","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,10,17]]},"assertion":[{"value":"2006-10-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}