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Related Experiment Video

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Measurement of Cytosolic Ca2+ in Isolated Contractile Lymphatics
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Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.

Dongwon Choi1,2, Eunkyung Park1,2, Roy P Yu1

  • 1Department 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.

Circulation Research
|June 15, 2022
PubMed
Summary
This summary is machine-generated.

The mechanosensor Piezo1 (Piezo type mechanosensitive ion channel component 1) regulates lymphatic growth by sensing fluid flow. Piezo1 activation offers a new therapy for postsurgical lymphedema.

Keywords:
calmodulinendothelial celllymphedemamechanotransduction, cellularmutation

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Area of Science:

  • Cardiovascular Biology
  • Cell Biology
  • Physiology

Background:

  • Mutations in PIEZO1 cause human lymphatic malformations.
  • A previously identified ORAI1-mediated pathway regulates lymphatic sprouting via Notch signaling in response to fluid flow.
  • The upstream mechanosensor for this pathway remained unidentified.

Purpose of the Study:

  • To identify and characterize the molecular sensor translating external mechanical signals to ORAI1-regulated lymphatic expansion.
  • To elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration.

Main Methods:

  • Utilized mutant mouse models, cellular and molecular biology techniques, and a mouse tail lymphedema model.
  • Investigated Piezo1 expression and function in lymphatic endothelial cells.
  • Examined the effects of Piezo1 manipulation on calcium influx and downstream gene expression.

Main Results:

  • Piezo1 is crucial for laminar flow-induced calcium influx and ORAI1-dependent gene regulation (KLF2, DTX1, DTX3L, NOTCH1) in lymphatic endothelial cells.
  • Piezo1 activation stimulates ORAI1-regulated mechanotransduction, and Piezo1 acts upstream of ORAI1.
  • Piezo1 deficiency impairs lymphatic sprouting during development and causes regression in adults; Piezo1 activation with Yoda1 ameliorates lymphedema.

Conclusions:

  • Piezo1 functions as the upstream mechanosensor in the lymphatic mechanotransduction pathway, controlling lymphatic growth in response to physical stimuli.
  • Piezo1 activation represents a potential therapeutic strategy for preventing postsurgical lymphedema.
  • The Piezo1-lymphangiogenesis mechanism provides insight into Piezo1-associated lymphatic malformations.