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In hemangioma endothelial cells, all these components are present, but are functionally compromised, so that the levels of <jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content>1 are extremely low and <jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content>2 signalling is constitutively active. Consequently, the levels of Hypoxia Inducible Factor (<jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>)\u20101\u03b1 and its transcriptional targets, <jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content>\u2010A and C\u2010X\u2010C motif chemokine 12 (CxCl12), are elevated and a positive <jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content>\u2010A feedback loop is established. Overexpression of <jats:styled-content style=\"fixed-case\">ANTXR<\/jats:styled-content>1, carrying a heterozygous Ala\u2010to\u2010Thr mutation, induces hemangioma\u2010like signalling in control endothelial cells; <jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content> signalling is normalized when wild\u2010type <jats:styled-content style=\"fixed-case\">ANTXR<\/jats:styled-content>1 is overexpressed in hemangioma cells. These findings suggest that <jats:styled-content style=\"fixed-case\">ANTXR<\/jats:styled-content>1 functions as a negative regulator of <jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content>\u2010A signalling. Studies of a mouse model of the Growth Retardation, Alopecia, Pseudo\u2010anodontia and Optic Atrophy (<jats:styled-content style=\"fixed-case\">GAPO<\/jats:styled-content>) syndrome, caused by the loss\u2010of\u2010function mutations in <jats:styled-content style=\"fixed-case\">ANTXR<\/jats:styled-content>1, as well as knock\u2010in mice carrying the Ala\u2010to\u2010Thr <jats:styled-content style=\"fixed-case\">ANTXR<\/jats:styled-content>1 mutation, confirm that <jats:styled-content style=\"fixed-case\">ANTXR<\/jats:styled-content>1 functions as a suppressor of <jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content>\u2010A signalling. Cutaneous endothelial cells isolated from <jats:styled-content style=\"fixed-case\">ANTXR<\/jats:styled-content>1\u2010deficient mice exhibit low levels of <jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content>1, elevated levels of <jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content>\u2010A, <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>\u20101\u03b1 and CxCl12 and activated <jats:styled-content style=\"fixed-case\">VEGFR<\/jats:styled-content>2 signalling as in hemangioma. Increased numbers of myeloid cells in the skin of <jats:styled-content style=\"fixed-case\">ANTXR<\/jats:styled-content>1\u2010deficient mice are associated with reduced vascularity and increased skin fibrosis, suggesting a mechanism for hemangioma involution and replacement by fibrotic scars. Through controlling <jats:styled-content style=\"fixed-case\">VEGF<\/jats:styled-content>\u2010A signalling and extracellular matrix synthesis, <jats:styled-content style=\"fixed-case\">ANTXR<\/jats:styled-content>1 is emerging as a key regulator of skeletal and connective tissue development and homeostasis.<\/jats:p>","DOI":"10.1111\/iep.12198","type":"journal-article","created":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T11:24:13Z","timestamp":1472729053000},"page":"296-302","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Fell\u2010Muir Lecture: Regulatory mechanisms of skeletal and connective tissue development and homeostasis \u2013 lessons from studies of human disorders"],"prefix":"10.1111","volume":"97","author":[{"given":"Bjorn R.","family":"Olsen","sequence":"first","affiliation":[{"name":"Department of Developmental Biology Harvard School of Dental Medicine Boston MA 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