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Decreased lymphatic HIF-2[alpha] accentuates lymphatic remodeling in lymphedema

The Journal of clinical investigation, 2020-10, Vol.130 (10), p.5562 [Peer Reviewed Journal]

COPYRIGHT 2020 American Society for Clinical Investigation ;COPYRIGHT 2020 American Society for Clinical Investigation ;ISSN: 0021-9738 ;EISSN: 1558-8238 ;DOI: 10.1172/JCI136164

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  • Title:
    Decreased lymphatic HIF-2[alpha] accentuates lymphatic remodeling in lymphedema
  • Author: Jiang, Xinguo ; Tian, Wen ; Granucci, Eric J ; Tu, Allen B ; Kim, Dongeon ; Dahms, Petra ; Pasupneti, Shravani ; Peng, Gongyong ; Kim, Yesl ; Lim, Amber H ; Espinoza, F. Hernan ; Cribb, Matthew ; Dixon, J. Brandon ; Rockson, Stanley G ; Semenza, Gregg L ; Nicolls, Mark R
  • Subjects: Development and progression ; Lymphedema
  • Is Part Of: The Journal of clinical investigation, 2020-10, Vol.130 (10), p.5562
  • Description: Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor 1[alpha] (HIF-1[alpha]), but a reduction of HIF-2[alpha] protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif2[alpha] exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif2[alpha] caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2[alpha] is an important mediator of lymphatic health. HIF-2[alpha] promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopoietin-1 (AngptT) gene therapy. Our study suggests that HIF-2[alpha] normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2[alpha] pathways in lymphedema could mitigate long-term pathology and disability.
  • Publisher: American Society for Clinical Investigation
  • Language: English
  • Identifier: ISSN: 0021-9738
    EISSN: 1558-8238
    DOI: 10.1172/JCI136164
  • Source: Geneva Foundation Free Medical Journals at publisher websites
    PubMed Central
    Alma/SFX Local Collection
    ProQuest Central
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