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Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.
Choi, Dongwon; Park, Eunkyung; Yu, Roy P; Cooper, Michael N; Cho, Il-Taeg; Choi, Joshua; Yu, James; Zhao, Luping; Yum, Ji-Eun Irene; Yu, Jin Suh; Nakashima, Brandon; Lee, Sunju; Seong, Young Jin; Jiao, Wan; Koh, Chester J; Baluk, Peter; McDonald, Donald M; Saraswathy, Sindhu; Lee, Jong Y; Jeon, Noo Li; Zhang, Zhenqian; Huang, Alex S; Zhou, Bin; Wong, Alex K; Hong, Young-Kwon.
Afiliación
  • Choi D; Department 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.
  • Park E; Department of Biochemistry and Molecular Medicine (D.C., E.P., I.-T.C., L.Z., J.-E.I.Y., J.S.Y., S.L., Y.J.S., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
  • Yu RP; Department 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.
  • Cooper MN; Department of Biochemistry and Molecular Medicine (D.C., E.P., I.-T.C., L.Z., J.-E.I.Y., J.S.Y., S.L., Y.J.S., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
  • Cho IT; Department 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.
  • Choi J; Department 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.
  • Yu J; Department 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.
  • Zhao L; Department of Biochemistry and Molecular Medicine (D.C., E.P., I.-T.C., L.Z., J.-E.I.Y., J.S.Y., S.L., Y.J.S., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
  • Yum JI; Department 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.
  • Yu JS; Department 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.
  • Nakashima B; Department 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.
  • Lee S; Department of Biochemistry and Molecular Medicine (D.C., E.P., I.-T.C., L.Z., J.-E.I.Y., J.S.Y., S.L., Y.J.S., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
  • Seong YJ; Department 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.
  • Jiao W; Department of Biochemistry and Molecular Medicine (D.C., E.P., I.-T.C., L.Z., J.-E.I.Y., J.S.Y., S.L., Y.J.S., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
  • Koh CJ; Department 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.
  • Baluk P; Department of Biochemistry and Molecular Medicine (D.C., E.P., I.-T.C., L.Z., J.-E.I.Y., J.S.Y., S.L., Y.J.S., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
  • McDonald DM; Department 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.
  • Saraswathy S; Department 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.
  • Lee JY; Department of Biochemistry and Molecular Medicine (D.C., E.P., I.-T.C., L.Z., J.-E.I.Y., J.S.Y., S.L., Y.J.S., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
  • Jeon NL; Department 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.
  • Zhang Z; Department of Biochemistry and Molecular Medicine (D.C., E.P., I.-T.C., L.Z., J.-E.I.Y., J.S.Y., S.L., Y.J.S., Y.-K.H.), Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles' CA.
  • Huang AS; Department 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.
  • Zhou B; Division of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX (C.J.K.).
  • Wong AK; Cardiovascular Research Institute, UCSF Helen Diller Family Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco' CA (P.B., D.M.M.).
  • Hong YK; Cardiovascular Research Institute, UCSF Helen Diller Family Comprehensive Cancer Center, and Department of Anatomy, University of California, San Francisco' CA (P.B., D.M.M.).
Circ Res ; 131(2): e2-e21, 2022 07 08.
Article en En | MEDLINE | ID: mdl-35701867
ABSTRACT

BACKGROUND:

Mutations 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.

METHODS:

Various 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.

RESULTS:

Piezo1 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.

CONCLUSIONS:

Piezo1 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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Vasos Linfáticos / Linfedema Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Circ Res Año: 2022 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Vasos Linfáticos / Linfedema Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Circ Res Año: 2022 Tipo del documento: Article