ArticleCirculation research2017
ORAI1 Activates Proliferation of Lymphatic Endothelial Cells in Response to Laminar Flow Through Krüppel-Like Factors 2 and 4.
Erratum issuedOpen access · bronzeAbstract read
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Article in Circulation research, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 58 papers.
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58citing papers in PubMed
3.1field-weighted citation impact, top 7% of its field
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Who cites it
58 citing papers in PubMed, 83 citations in OpenAlex.
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Corrections and comments
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Authors and funding
16 authors at 4 institutions in 1 country.
Dongwon ChoiFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Eunkyung ParkFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Eunson JungFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Young Jin SeongFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Mingu HongFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Sunju LeeFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
James BurfordFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Georgina GyarmatiFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Janos Peti-PeterdiFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Sonal SrikanthFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Yousang GwackFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Chester J KohFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Evgenii BoriushkinFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Anne HamikFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Alex K WongFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.). alex.wong@med.usc.edu young.hong@usc.edu.
Young-Kwon HongFrom the Section of Plastic and Reconstructive Surgery, Department of Surgery (D.C., E.P., E.J., Y.J.S., M.H., S.L., A.K.W., Y.-K.H.), Department of Biochemistry and Molecular Biology (D.C., E.P., E.J., Y.J.S., M.H., S.L., Y.-K.H.), Norris Comprehensive Cancer Center, and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute (J.B., G.G., J.P.-P.), Keck School of Medicine, University of Southern California, Los Angeles; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, CA (S.S., Y.G.); Department of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston (C.J.K.); Division of Cardiovascular Medicine, Department of Medicine, Stony Brook University, NY (E.B., A.H.); and Northport Veterans Affairs Medical Center, NY (A.H.).
Stony Brook University · USBaylor College of Medicine · USTexas Children's Hospital · USUniversity of California, Los Angeles · US
Funding
USC/NORRIS COMPREHENSIVE CANCER CENTER (CORE) SUPPORTP30CA014089 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI MYLES G COCKBURN · 1985 to 2026
$181.4MRetinoic acid signaling in lymphangiogenesisR01HL121036 · NHLBI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HONG, YOUNG-KWON · 2014 to 2017
$1.7MFlow Dependent Development and Maintenance of Schlemm's CanalR21EY026260 · NEI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HONG, YOUNG-KWON · 2016 to 2017
$454kEarly Detection and Intervention of Surgery-Induced Lymphatic InsufficiencyR21HL119583 · NHLBI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HONG, YOUNG-KWON · 2014 to 2015
$451kDistinct functions of Orai1 and Orai2 in naive and effector helper T cellsR21AI130653 · NIAID · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI SRIKANTH, SONAL · 2017 to 2018
$424kNCI NIH HHS P30 CA014089NEI NIH HHS R21 EY026260NHLBI NIH HHS R01 HL121036NHLBI NIH HHS R21 HL119583NIAID NIH HHS R21 AI130653
Abstract
rationaleLymphatic vessels function to drain interstitial fluid from a variety of tissues. Although shear stress generated by fluid flow is known to trigger lymphatic expansion and remodeling, the molecular basis underlying flow-induced lymphatic growth is unknown.
objectiveWe aimed to gain a better understanding of the mechanism by which laminar shear stress activates lymphatic proliferation. METHODS AND
resultsPrimary endothelial cells from dermal blood and lymphatic vessels (blood vascular endothelial cells and lymphatic endothelial cells [LECs]) were exposed to low-rate steady laminar flow. Shear stress-induced molecular and cellular responses were defined and verified using various mutant mouse models. Steady laminar flow induced the classic shear stress responses commonly in blood vascular endothelial cells and LECs. Surprisingly, however, only LECs showed enhanced cell proliferation by regulating the vascular endothelial growth factor (VEGF)-A, VEGF-C, FGFR3, and p57/CDKN1C genes. As an early signal mediator, ORAI1, a pore subunit of the calcium release-activated calcium channel, was identified to induce the shear stress phenotypes and cell proliferation in LECs responding to the fluid flow. Mechanistically, ORAI1 induced upregulation of Krüppel-like factor (KLF)-2 and KLF4 in the flow-activated LECs, and the 2 KLF proteins cooperate to regulate VEGF-A, VEGF-C, FGFR3, and p57 by binding to the regulatory regions of the genes. Consistently, freshly isolated LECs from
conclusionsOur study identified a molecular mechanism for laminar flow-activated LEC proliferation.
Indexed as
Cell ProliferationLymphangiogenesisMechanotransduction, CellularAnimalsCyclin-Dependent Kinase Inhibitor p57Endothelial CellsEndothelium, LymphaticEndothelium, VascularGene Expression RegulationGenotypeHumansHuman Umbilical Vein Endothelial CellsKruppel-Like Factor 4Kruppel-Like Transcription FactorsMice, KnockoutORAI1 ProteinCdkn1c protein, mouseCyclin-Dependent Kinase Inhibitor p57Fgfr3 protein, mouseKlf2 protein, mouseKLF4 protein, humanKlf4 protein, mouseKruppel-Like Factor 4Kruppel-Like Transcription FactorsORAI1 ProteinOrai1 protein, mouseReceptor, Fibroblast Growth Factor, Type 3Vascular Endothelial Growth Factor Avascular endothelial growth factor A, mouseVascular Endothelial Growth Factor Cvascular endothelial growth factor C, mousecalcium channelcapillarycell proliferationlymphatic vesselsvascular endothelial growth factor A
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