Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance
Dongwon Choi, … , Il-Taeg Cho, Young-Kwon Hong
Dongwon Choi, … , Il-Taeg Cho, Young-Kwon Hong
Published January 24, 2019
Citation Information: JCI Insight. 2019;4(5):e125068. https://doi.org/10.1172/jci.insight.125068.
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Research Article Vascular biology

Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance

Abstract

The lymphatic system plays crucial roles in tissue homeostasis, lipid absorption, and immune cell trafficking. Although lymphatic valves ensure unidirectional lymph flows, the flow itself controls lymphatic valve formation. Here, we demonstrate that a mechanically activated ion channel Piezo1 senses oscillating shear stress (OSS) and incorporates the signal into the genetic program controlling lymphatic valve development and maintenance. Time-controlled deletion of Piezo1 using a pan-endothelial Cre driver (Cdh5[PAC]-CreERT2) or lymphatic-specific Cre driver (Prox1-CreERT2) equally inhibited lymphatic valve formation in newborn mice. Furthermore, Piezo1 deletion in adult lymphatics caused substantial lymphatic valve degeneration. Piezo1 knockdown in cultured lymphatic endothelial cells (LECs) largely abrogated the OSS-induced upregulation of the lymphatic valve signature genes. Conversely, ectopic Piezo1 overexpression upregulated the lymphatic valve genes in the absence of OSS. Remarkably, activation of Piezo1 using chemical agonist Yoda1 not only accelerated lymphatic valve formation in animals, but also triggered upregulation of some lymphatic valve genes in cultured LECs without exposure to OSS. In summary, our studies together demonstrate that Piezo1 is the force sensor in the mechanotransduction pathway controlling lymphatic valve development and maintenance, and Piezo1 activation is a potentially novel therapeutic strategy for congenital and surgery-associated lymphedema.

Authors

Dongwon Choi, Eunkyung Park, Eunson Jung, Boksik Cha, Somin Lee, James Yu, Paul M. Kim, Sunju Lee, Yeo Jin Hong, Chester J. Koh, Chang-Won Cho, Yifan Wu, Noo Li Jeon, Alex K. Wong, Laura Shin, S. Ram Kumar, Ivan Bermejo-Moreno, R. Sathish Srinivasan, Il-Taeg Cho, Young-Kwon Hong

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Figure 2

Piezo1 deletion in lymphatic valves by low-dose tamoxifen.

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Piezo1 deletion in lymphatic valves by low-dose tamoxifen. (A–D) Dermal...
(A–D) Dermal lymphatics in the ear of Piezo1-tdTomato adult reporter mouse Piezo1P1−tdT (26) were immunostained for tdTomato protein (to amplify the reporter signal) and Prox1 (to detect LECs). Images were captured by an (A and B) epifluorescence or (C and D) confocal microscope. Note an enriched expression of Piezo1-tdTomato fusion protein in Prox1hi valve leaflet LECs. (E–N) Piezo1 deletion by low-dose tamoxifen suppressed lymphatic valve formation with a minimal effect on lymphatic vessel density. (E) Experimental design: Peizo1 deletion was induced by low-dose tamoxifen injection (15 mg/kg) in the control and lymphatic Piezo1-KO pups at P1, and the mesenteric lymphatic valves in the jejunum and colon were analyzed at P7. (F–M) Piezo1 deletion suppressed lymphatic valve formation in the mesenteries of the (F–I) jejunum and (J–M) colon. Boxed areas were enlarged in panels below, respectively. Arrows mark matured lymphatic valves. (N) Quantitation of lymphatic valves in the control and lymphatic Piezo1-KO pups for panels F–M. The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range. The lymphatics were visualized by Prox1-tdTomato, and the signal was expressed in inverted grayscale. Scale bars: 100 μm (A–D), 500 μm (F–M). ***P < 0.001, unpaired, 2-tailed t test compared with the valve of the controls. Three pups were used for each group. A representative of >10 images was chosen for each panel.