Seung-Hun Lee1, Sungsu Lee1, Hanseul Yang1, Sukhyun Song1, Kangsan Kim1, Thomas L Saunders1, Jeong K Yoon1, Gou Young Koh2, Injune Kim2. 1. From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.). 2. From the Graduate School of Medical Science and Engineering (S.-H.L., S.L., H.Y., S.S., K.K., G.Y.K., I.K.) and Biomedical Science and Engineering Interdisciplinary Program (S.-H.L., G.Y.K., I.K.), Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Department of Otolaryngology-Head and Neck Surgery, Chonnam National University Hospital, Gwangju, Republic of Korea (S.L.); Transgenic Animal Model Core, University of Michigan, Ann Arbor (T.L.S.); and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough (J.K.Y.) injunek@kaist.ac.kr gykoh@kaist.ac.kr.
Abstract
RATIONALE: The Notch pathway stabilizes sprouting angiogenesis by favoring stalk cells over tip cells at the vascular front. Because tip and stalk cells have different properties in morphology and function, their transcriptional regulation remains to be distinguished. Transcription factor Sox17 is specifically expressed in endothelial cells, but its expression and role at the vascular front remain largely unknown. OBJECTIVE: To specify the role of Sox17 and its relationship with the Notch pathway in sprouting angiogenesis. METHODS AND RESULTS: Endothelial-specific Sox17 deletion reduces sprouting angiogenesis in mouse embryonic and postnatal vascular development, whereas Sox17 overexpression increases it. Sox17 promotes endothelial migration by destabilizing endothelial junctions and rearranging cytoskeletal structure and upregulates expression of several genes preferentially expressed in tip cells. Interestingly, Sox17 expression is suppressed in stalk cells in which Notch signaling is relatively high. Notch activation by overexpressing Notch intracellular domain reduces Sox17 expression both in primary endothelial cells and in retinal angiogenesis, whereas Notch inhibition by delta-like ligand 4 (Dll4) blockade increases it. The Notch pathway regulates Sox17 expression mainly at the post-transcriptional level. Furthermore, endothelial Sox17 ablation rescues vascular network from excessive tip cell formation and hyperbranching under Notch inhibition in developmental and tumor angiogenesis. CONCLUSIONS: Our findings demonstrate that the Notch pathway restricts sprouting angiogenesis by reducing the expression of proangiogenic regulator Sox17.
RATIONALE: The Notch pathway stabilizes sprouting angiogenesis by favoring stalk cells over tip cells at the vascular front. Because tip and stalk cells have different properties in morphology and function, their transcriptional regulation remains to be distinguished. Transcription factor Sox17 is specifically expressed in endothelial cells, but its expression and role at the vascular front remain largely unknown. OBJECTIVE: To specify the role of Sox17 and its relationship with the Notch pathway in sprouting angiogenesis. METHODS AND RESULTS: Endothelial-specific Sox17 deletion reduces sprouting angiogenesis in mouse embryonic and postnatal vascular development, whereas Sox17 overexpression increases it. Sox17 promotes endothelial migration by destabilizing endothelial junctions and rearranging cytoskeletal structure and upregulates expression of several genes preferentially expressed in tip cells. Interestingly, Sox17 expression is suppressed in stalk cells in which Notch signaling is relatively high. Notch activation by overexpressing Notch intracellular domain reduces Sox17 expression both in primary endothelial cells and in retinal angiogenesis, whereas Notch inhibition by delta-like ligand 4 (Dll4) blockade increases it. The Notch pathway regulates Sox17 expression mainly at the post-transcriptional level. Furthermore, endothelial Sox17 ablation rescues vascular network from excessive tip cell formation and hyperbranching under Notch inhibition in developmental and tumor angiogenesis. CONCLUSIONS: Our findings demonstrate that the Notch pathway restricts sprouting angiogenesis by reducing the expression of proangiogenic regulator Sox17.
Authors: Ivy Kim-Ni Chiang; Martin Fritzsche; Cathy Pichol-Thievend; Alice Neal; Kelly Holmes; Anne Lagendijk; Jeroen Overman; Donatella D'Angelo; Alice Omini; Dorien Hermkens; Emmanuelle Lesieur; Ke Liu; Indrika Ratnayaka; Monica Corada; George Bou-Gharios; Jason Carroll; Elisabetta Dejana; Stefan Schulte-Merker; Benjamin Hogan; Monica Beltrame; Sarah De Val; Mathias Francois Journal: Development Date: 2017-06-15 Impact factor: 6.868
Authors: Ashley S Robinson; Stefan C Materna; Ralston M Barnes; Sarah De Val; Shan-Mei Xu; Brian L Black Journal: Dev Biol Date: 2014-08-30 Impact factor: 3.582