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In vivo, reduction in interdigital vessel number inhibited PCD, resulting in syndactyly, whereas an increment in vessel number and distribution resulted in elevation and expansion of PCD. Production of reactive oxygen species (ROS), toxic compounds that have been implicated in PCD, also depended on interdigital vascular patterning. Finally, ex vivo incubation of limbs in gradually decreasing oxygen levels led to a correlated reduction in both ROS production and interdigital PCD. The results support a role for oxygen in these processes and provide a mechanistic explanation for the counterintuitive positive role of the vasculature in PCD. In conclusion, we suggest a new role for vascular patterning during limb development in regulating interdigital PCD by ROS production. More broadly, we propose a double safety mechanism that restricts PCD to interdigital areas, as the genetic program of PCD provides the first layer and vascular patterning serves as the second.<\/jats:p>","DOI":"10.1242\/dev.120279","type":"journal-article","created":{"date-parts":[[2015,1,24]],"date-time":"2015-01-24T00:43:20Z","timestamp":1422060200000},"source":"Crossref","is-referenced-by-count":11,"title":["Vascular patterning regulates interdigital cell death by a ROS-mediated mechanism"],"prefix":"10.1242","author":[{"given":"Idit","family":"Eshkar-Oren","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Krief","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Napoleone","family":"Ferrara","sequence":"additional","affiliation":[{"name":"Genentech, Inc., 1 DNA Way, S. 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