title: Flow-Dependent Endothelial YAP Regulation Contributes to Vessel Maintenance.
abstract: Endothelial cells (ECs) line the inside of blood vessels and respond to mechanical cues generated by blood flow. Mechanical stimuli regulate the localization of YAP by reorganizing the actin cytoskeleton. Here we demonstrate blood-flow-mediated regulation of endothelial YAP in vivo. We indirectly monitored transcriptional activity of Yap1 (zebrafish YAP) and its spatiotemporal localization in living zebrafish and found that Yap1 entered the nucleus and promoted transcription in response to blood flow. In cultured human ECs, laminar shear stress induced nuclear import of YAP and its transcriptional activity in a manner independent of Hippo signaling. We uncovered a molecular mechanism by which flow induced the nuclear translocation of YAP through the regulation of filamentous actin and angiomotin. Yap1 mutant zebrafish showed a defect in vascular stability, indicating an essential role for Yap1 in blood vessels. Our data imply that endothelial Yap1 functions in response to flow to maintain blood vessels.
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Laboratory of System Physiology, Department of Biomedical Engineering, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Developmental Biology, SFB850, Institute for Biology I, Albert Ludwigs University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Sobhika
authors.initials: S
authors.lastname: Agarwala
authors.affiliation: Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8315, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Terai
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Fukui
authors.affiliation: Department of Molecular Pathophysiology, Nippon Medical School, Kawasaki, Kanagawa 211-8533, Japan.
authors.forename: Shigetomo
authors.initials: S
authors.lastname: Fukuhara
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ando
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yokota
authors.affiliation: Biozentrum der Universität Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Etienne
authors.initials: E
authors.lastname: Schmelzer
authors.affiliation: Biozentrum der Universität Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Heinz-Georg
authors.initials: HG
authors.lastname: Belting
authors.affiliation: Biozentrum der Universität Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Affolter
authors.affiliation: Department of Developmental Biology of Vertebrates, Institute for Cell Biology and Neurosciences, Goethe University of Frankfurt, 60438 Frankfurt, Germany.
authors.forename: Virginie
authors.initials: V
authors.lastname: Lecaudey
authors.affiliation: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan; AMED-CREST, National Cerebral and Cardiovascular Center, 5-7-1, Suita, Osaka 565-8565, Japan. Electronic address: nmochizu@ri.ncvc.go.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D018056:Hemorheology; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010477:Perfusion; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D000090742:Serine-Threonine Kinase 3; D033081:Shear Strength; D015398:Signal Transduction / Q000235:genetics; D013314:Stress, Mechanical; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000235:genetics; D000091102:YAP-Signaling Proteins; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D000090742:Serine-Threonine Kinase 3; D015534:Trans-Activators; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; D029961:Zebrafish Proteins; C088374:YAP1 protein, human; C583457:Yes-associated protein (yap), zebrafish; C543122:amot protein, zebrafish; C541414:stk3 protein, zebrafish; D000099317:Hippo Kinases
keywords: Hippo pathway; fluid shear stress; mechanotransduction; vascular remodeling