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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.

Background: Combining abdominoplasty with liposuction is a common practice for optimal patient aesthetic outcomes. In the past, several practitioners have argued against liposuction due to the potential for vascular insufficiency, especially with central liposuction. Despite these concerns for flap damage with resultant necrosis, the incidence of this complication has not been comprehensively investigated.Objectives: The authors therefore examined the incidence of necrotic complications, including skin and fat necrosis as well as partial/total flap loss, in patients who underwent abdominoplasty alone (AA) or abdominoplasty with partial or circumferential liposuction (APCL).Methods: Literature searches were performed in PubMed/Medline and Embase with no query limits. For the systematic review, data from the studies were extracted into a form including primary author, publication year, study design, number of AA and APCL patients, abdominal zone(s) treated with liposuction, average lipoaspirate volume, follow-up time, necrotic complications, and revision procedures. A meta-analysis was separately performed for 13 studies that included patients who underwent both AA and APCL.Results: The overall rate of necrotic complications was lower in the APCL group (0.39%) compared with the AA group (1.01%). The incidence of necrotic complications was low for all patients, with a pooled partial flap loss rate of 0.24% and a pooled skin necrosis rate of 0.23%. The forest plots revealed that patients who underwent APCL do not face a higher risk of skin necrosis or revision compared with those who underwent AA.Conclusions: Performing APCL is a safe combined procedural approach and can confer added benefits of improved patient satisfaction and aesthetic outcomes.Level Of Evidence:4: [ABSTRACT FROM AUTHOR]