{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:42:43Z","timestamp":1790664163075,"version":"4.1.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>Evidences accumulated within the past decades identified hedgehog signaling as a new regulator of endothelium integrity. More specifically, we recently identified Dhh (desert hedgehog) as a downstream effector of Klf2 (Kruppel-like factor 2) in endothelial cells (ECs). The purpose of this study is to investigate whether hedgehog coreceptors Gas1 (growth arrest-specific 1) and Cdon (cell adhesion molecule-related\/downregulated by oncogenes) may be used as therapeutic targets to modulate Dhh signaling in ECs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results:<\/jats:title>\n                    <jats:p>We demonstrated that both Gas1 and Cdon are expressed in adult ECs and relied on either siRNAs- or EC-specific conditional knockout mice to investigate their role. We found that Gas1 deficiency mainly phenocopies Dhh deficiency especially by inducing VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) overexpression while Cdon deficiency has opposite effects by promoting endothelial junction integrity. At a molecular level, Cdon prevents Dhh binding to Ptch1 (patched-1) and thus acts as a decoy receptor for Dhh, while Gas1 promotes Dhh binding to Smo (smoothened) and as a result potentiates Dhh effects. Since Cdon is upregulated in ECs treated by inflammatory cytokines, including TNF (tumor necrosis factor)-\u03b1 and Il (interleukin)-1\u03b2, we then tested whether Cdon inhibition would promote endothelium integrity in acute inflammatory conditions and found that both fibrinogen and IgG extravasation were decreased in association with an increased Cdh5 (cadherin-5) expression in the brain cortex of EC-specific Cdon knockout mice administered locally with Il-1\u03b2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Altogether, these results demonstrate that Gas1 is a positive regulator of Dhh in ECs while Cdon is a negative regulator. Interestingly, Cdon blocking molecules may then be used to promote endothelium integrity, at least in inflammatory conditions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.120.314441","type":"journal-article","created":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T05:00:52Z","timestamp":1602133252000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["Desert Hedgehog-Driven Endothelium Integrity Is Enhanced by Gas1 (Growth Arrest-Specific 1) but Negatively Regulated by Cdon (Cell Adhesion Molecule-Related\/Downregulated by Oncogenes)"],"prefix":"10.1161","volume":"40","author":[{"given":"Candice","family":"Chapouly","sequence":"first","affiliation":[{"name":"University of Bordeaux, Inserm, Biology of Cardiovascular Diseases, U1034, F-33604 Pessac, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Louis","family":"Hollier","sequence":"additional","affiliation":[{"name":"University of Bordeaux, Inserm, Biology of Cardiovascular Diseases, U1034, F-33604 Pessac, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Guimbal","sequence":"additional","affiliation":[{"name":"University of Bordeaux, Inserm, Biology of Cardiovascular Diseases, U1034, F-33604 Pessac, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauriane","family":"Cornuault","sequence":"additional","affiliation":[{"name":"University of Bordeaux, Inserm, Biology of Cardiovascular Diseases, U1034, F-33604 Pessac, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain-Pierre","family":"Gadeau","sequence":"additional","affiliation":[{"name":"University of Bordeaux, Inserm, Biology of Cardiovascular Diseases, U1034, F-33604 Pessac, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Ange","family":"Renault","sequence":"additional","affiliation":[{"name":"University of Bordeaux, Inserm, Biology of Cardiovascular Diseases, U1034, F-33604 Pessac, France."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.312580"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20123076"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1206936"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0068891"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvv263"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.313177"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1101\/2020.03.13.990762"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190730"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2008.05.528"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1101\/2020.03.03.974444"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/287795a0"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2002906"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.3390\/jdb4030023"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2012.01.019"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.201418298"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1418629112"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.103242"},{"key":"e_1_3_4_19_2","first-page":"1625","article-title":"A model of angiogenesis in the mouse cornea.","volume":"37","author":"Kenyon BM","year":"1996","unstructured":"Kenyon, BM, Voest, EE, Chen, CC, Flynn, E, Folkman, J, D\u2019Amato, RJ. 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