Evidence map›Paper›PMID 35701867›Full record

ArticleCirculation research2022

Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.

Dongwon Choi, Eunkyung Park, Roy P Yu, Michael N Cooper, Il-Taeg Cho, Joshua Choi, James Yu, Luping Zhao, Ji-Eun Irene Yum, Jin Suh Yu and 15 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
57citing papers in PubMed, 1 pooled it
8.2field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

57 citing papers in PubMed, 1 synthesis or guideline pooled it, 90 citations in OpenAlex.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

25 authors at 7 institutions in 4 countries.

Dongwon ChoiDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Eunkyung ParkDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Roy P YuDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Michael N CooperDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Il-Taeg ChoDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Joshua ChoiDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
James YuDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.ORCID 0000-0001-5906-754X
Luping ZhaoDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Ji-Eun Irene YumDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Jin Suh YuDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Brandon NakashimaDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Sunju LeeDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Young Jin SeongDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Wan JiaoDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
Chester J KohDivision of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX (C.J.K.).
Peter BalukCardiovascular Research Institute, UCSF Helen Diller Family Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco' CA (P.B., D.M.M.).
Donald M McDonaldCardiovascular Research Institute, UCSF Helen Diller Family Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco' CA (P.B., D.M.M.).
Sindhu SaraswathyDoheny Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA' Los Angeles' CA (S.S., J.Y.L., A.S.H.).
Jong Y LeeDoheny Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA' Los Angeles' CA (S.S., J.Y.L., A.S.H.).ORCID 0000-0001-5629-5117
Noo Li JeonDepartment of Mechanical and Aerospace Engineering, Seoul National University, Republic of Korea (N.L.J.).
Zhenqian ZhangState Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China (Z.Z., B.Z.).
Alex S HuangDoheny Eye Institute and Department of Ophthalmology, David Geffen School of Medicine at UCLA' Los Angeles' CA (S.S., J.Y.L., A.S.H.).
Bin ZhouState Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, China (Z.Z., B.Z.).
Alex K WongDivision of Plastic Surgery, City of Hope National Medical Center, Duarte, CA (A.K.W.).ORCID 0000-0002-4068-5230
Young-Kwon HongDepartment of Surgery (D.C., E.P., R.P.Y., M.N.C., I.-T.C., J.C., J.Y., L.Z., J.-E.I.Y., J.S.Y., B.N., S.L., Y.J.S., W.J., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.ORCID 0000-0001-8245-875X
University of Southern California · USDoheny Eye Institute · USCenter for Excellence in Molecular Cell Science · CNUCSF Helen Diller Family Comprehensive Cancer Center · USCity Of Hope National Medical Center · USSeoul National University · KRTexas Children's Hospital · US

Funding

Mentored Career DevelopmentKL2TR001854 · NCATS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Elizabeth Rhea Erwin Burner, Amy Elizabeth West · 2016 to 2026
$9.0M
ENDOTHELIAL PERMEABILITY IN AIRWAY ANGIOGENESISR01HL059157 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MCDONALD, DONALD M · 1998 to 2015
$5.5M
Structural and Functional Studies of the Uterine LymphaticsR01HL141857 · NHLBI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Young-Kwon Hong · 2018 to 2026
$3.6M
Dynamic Variable Aqueous Humor Outflow and Glaucoma Therapies in the Human EyeR01EY030501 · NEI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI Alex Huang, Hao F Zhang · 2020 to 2026
$3.5M
(PQ6) vGPCR-Mediated Paracrine Transformation for Kaposi SarcomaR01CA250065 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HONG, YOUNG-KWON · 2020 to 2024
$3.3M
Retinoic Acid Induced Lymphangiogenesis for Post-Surgical LymphedemaR01HL157626 · NHLBI · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · PI WONG, ALEX K. · 2021 to 2025
$3.2M
Angiopoietin/Tie signaling regulation of vascular leakage in lung inflammationR01HL143896 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MCDONALD, DONALD M · 2018 to 2021
$2.5M
Mechanisms, consequences, and reversal of abnormalities in lung lymphaticsR01HL127402 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MCDONALD, DONALD M · 2015 to 2018
$2.2M
USC Stimulating Access to Research in Residency (USC-StARR) ProgramR38HL155773 · NHLBI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI Fumito Ito, Sanjeet Patel · 2021 to 2026
$2.2M
Prox1 Phosphorylation in Lymphatic Development and FunctionR01DK114645 · NIDDK · UNIVERSITY OF SOUTHERN CALIFORNIA · PI HONG, YOUNG-KWON · 2018 to 2022
$2.1M
Investigation of 9-cis Retinoic Acid as a Novel Treatment for Post-Surgical LymphedemaK08HL132110 · NHLBI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI WONG, ALEX K. · 2017 to 2020
$712k
NCATS NIH HHS KL2 TR001854NCI NIH HHS R01 CA250065NEI NIH HHS R01 EY030501NHLBI NIH HHS K08 HL132110NHLBI NIH HHS R01 HL059157NHLBI NIH HHS R01 HL127402NHLBI NIH HHS R01 HL141857NHLBI NIH HHS R01 HL143896NHLBI NIH HHS R01 HL157626NHLBI NIH HHS R38 HL155773NIDDK NIH HHS R01 DK114645
6 · The paper itself

Abstract

backgroundMutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion.

methodsVarious mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration.

resultsPiezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development.

conclusionsPiezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.

Indexed as

Lymphatic VesselsLymphedemaAnimalsEndothelial CellsHumansIon ChannelsMechanotransduction, CellularMiceTranscription FactorsUbiquitin-Protein LigasesIon ChannelsPiezo1 protein, mouseTranscription FactorsUbiquitin-Protein Ligasescalmodulinendothelial celllymphedemamechanotransduction, cellularmutation

Identifiers

PMID35701867
PMCPMC9308715
OpenAlexW4282926850

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.