M. Cossutta, Marie Darche, G. Carpentier, Claire Houppe, Matteo Ponzo, F. Raineri, B. Vallée, Maud-Emmanuelle Gilles, Delphine Villain, É. Picard, C. Casari, C. Denis, M. Pâques, J. Courty, Ilaria Cascone
{"title":"血管生成过程中,韦贝尔-帕拉德体协调周细胞。","authors":"M. Cossutta, Marie Darche, G. Carpentier, Claire Houppe, Matteo Ponzo, F. Raineri, B. Vallée, Maud-Emmanuelle Gilles, Delphine Villain, É. Picard, C. Casari, C. Denis, M. Pâques, J. Courty, Ilaria Cascone","doi":"10.1161/ATVBAHA.119.313021","DOIUrl":null,"url":null,"abstract":"Objective Weibel-Palade Bodies (WPBs) are endothelial cell (EC)-specific organelles formed by Vwf (von Willebrand Factor) polymerization and that contain the proangiogenic factor Ang-2 (angiopoietin-2). WPB exocytosis has been shown to be implicated for vascular repair and inflammatory responses. Here, we investigate the role of WPBs during angiogenesis and vessel stabilization. Approach and Results WPB density in ECs decreased at the angiogenic front of retinal vascular network during development and reneovascularization compared with stable vessels. In vitro, VEGF induced a VEGFR-2-dependent exocytosis of WPBs that contain Ang-2 and consequently the secretion of vWF and Ang-2. Blocking VEGF-dependant WPB exocytosis and Ang-2 secretion promoted pericyte migration toward ECs. Pericyte migration was inhibited by adding recombinant Ang-2 or by silencing Ang-1 (angiopoietin-1) or Tie2 in pericytes. Consistently, in vivo anti-VEGF treatment induced accumulation of WPBs in retinal vessels because of the inhibition of WPB exocytosis and promoted the increase of pericyte coverage of retinal vessels during angiogenesis. In tumor angiogenesis, depletion of WPBs in vWF knockout tumor-bearing mice promoted an increase of tumor angiogenesis and a decrease of pericyte coverage of tumor vessel. By another approach, normalized tumor vessels had higher WPB density. Conclusions We demonstrate that WPB exocytosis and Ang-2 secretion are regulated during angiogenesis to limit pericyte coverage of remodeling vessels by disrupting Ang-1/Tie2 autocrine signaling in pericytes.","PeriodicalId":8404,"journal":{"name":"Arteriosclerosis, Thrombosis, & Vascular Biology","volume":"29 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2019-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"17","resultStr":"{\"title\":\"Weibel-Palade Bodies Orchestrate Pericytes During Angiogenesis.\",\"authors\":\"M. Cossutta, Marie Darche, G. Carpentier, Claire Houppe, Matteo Ponzo, F. Raineri, B. Vallée, Maud-Emmanuelle Gilles, Delphine Villain, É. Picard, C. Casari, C. Denis, M. Pâques, J. Courty, Ilaria Cascone\",\"doi\":\"10.1161/ATVBAHA.119.313021\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Objective Weibel-Palade Bodies (WPBs) are endothelial cell (EC)-specific organelles formed by Vwf (von Willebrand Factor) polymerization and that contain the proangiogenic factor Ang-2 (angiopoietin-2). WPB exocytosis has been shown to be implicated for vascular repair and inflammatory responses. Here, we investigate the role of WPBs during angiogenesis and vessel stabilization. Approach and Results WPB density in ECs decreased at the angiogenic front of retinal vascular network during development and reneovascularization compared with stable vessels. In vitro, VEGF induced a VEGFR-2-dependent exocytosis of WPBs that contain Ang-2 and consequently the secretion of vWF and Ang-2. Blocking VEGF-dependant WPB exocytosis and Ang-2 secretion promoted pericyte migration toward ECs. Pericyte migration was inhibited by adding recombinant Ang-2 or by silencing Ang-1 (angiopoietin-1) or Tie2 in pericytes. Consistently, in vivo anti-VEGF treatment induced accumulation of WPBs in retinal vessels because of the inhibition of WPB exocytosis and promoted the increase of pericyte coverage of retinal vessels during angiogenesis. In tumor angiogenesis, depletion of WPBs in vWF knockout tumor-bearing mice promoted an increase of tumor angiogenesis and a decrease of pericyte coverage of tumor vessel. By another approach, normalized tumor vessels had higher WPB density. Conclusions We demonstrate that WPB exocytosis and Ang-2 secretion are regulated during angiogenesis to limit pericyte coverage of remodeling vessels by disrupting Ang-1/Tie2 autocrine signaling in pericytes.\",\"PeriodicalId\":8404,\"journal\":{\"name\":\"Arteriosclerosis, Thrombosis, & Vascular Biology\",\"volume\":\"29 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2019-07-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"17\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Arteriosclerosis, Thrombosis, & Vascular Biology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1161/ATVBAHA.119.313021\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arteriosclerosis, Thrombosis, & Vascular Biology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1161/ATVBAHA.119.313021","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Weibel-Palade Bodies Orchestrate Pericytes During Angiogenesis.
Objective Weibel-Palade Bodies (WPBs) are endothelial cell (EC)-specific organelles formed by Vwf (von Willebrand Factor) polymerization and that contain the proangiogenic factor Ang-2 (angiopoietin-2). WPB exocytosis has been shown to be implicated for vascular repair and inflammatory responses. Here, we investigate the role of WPBs during angiogenesis and vessel stabilization. Approach and Results WPB density in ECs decreased at the angiogenic front of retinal vascular network during development and reneovascularization compared with stable vessels. In vitro, VEGF induced a VEGFR-2-dependent exocytosis of WPBs that contain Ang-2 and consequently the secretion of vWF and Ang-2. Blocking VEGF-dependant WPB exocytosis and Ang-2 secretion promoted pericyte migration toward ECs. Pericyte migration was inhibited by adding recombinant Ang-2 or by silencing Ang-1 (angiopoietin-1) or Tie2 in pericytes. Consistently, in vivo anti-VEGF treatment induced accumulation of WPBs in retinal vessels because of the inhibition of WPB exocytosis and promoted the increase of pericyte coverage of retinal vessels during angiogenesis. In tumor angiogenesis, depletion of WPBs in vWF knockout tumor-bearing mice promoted an increase of tumor angiogenesis and a decrease of pericyte coverage of tumor vessel. By another approach, normalized tumor vessels had higher WPB density. Conclusions We demonstrate that WPB exocytosis and Ang-2 secretion are regulated during angiogenesis to limit pericyte coverage of remodeling vessels by disrupting Ang-1/Tie2 autocrine signaling in pericytes.