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

Autor:	Choi D; Department of Surgery, and.; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA., Park E; Department of Surgery, and.; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA., Jung E; Department of Surgery, and.; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA., Cha B; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA., Lee S; Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul, South Korea., Yu J; Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul, South Korea., Kim PM; Department of Surgery, and.; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA., Lee S; Department of Surgery, and.; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA., Hong YJ; Department of Surgery, and.; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA., Koh CJ; Division of Pediatric Urology, Texas Children's Hospital, Baylor Collexge of Medicine, Houston, Texas, USA., Cho CW; Department of Surgery, and.; Traditional Food Research Group, Korea Food Research Institute, Wanju-gun, Jeollabuk-do, South Korea., Wu Y; Department of Surgery, and.; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA., Li Jeon N; Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul, South Korea., Wong AK; Department of Surgery, and., Shin L; Department of Surgery, and., Kumar SR; Department of Surgery, and., Bermejo-Moreno I; Department of Aerospace and Mechanical Engineering, University of Southern California, Los Angeles, California, USA., Srinivasan RS; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA., Cho IT; Department of Surgery, and., Hong YK; Department of Surgery, and.; Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, UCLA, Los Angeles, California, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2019 Mar 07; Vol. 4 (5). Date of Electronic Publication: 2019 Mar 07 (Print Publication: 2019).
DOI:	10.1172/jci.insight.125068
Abstrakt:	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.
Databáze:	MEDLINE
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