Decreased lymphatic HIF-2α accentuates lymphatic remodeling in lymphedema
Xinguo Jiang, … , Gregg L. Semenza, Mark R. Nicolls
Xinguo Jiang, … , Gregg L. Semenza, Mark R. Nicolls
Published July 16, 2020
Citation Information: J Clin Invest. 2020;130(10):5562-5575. https://doi.org/10.1172/JCI136164.
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Research Article Inflammation Vascular biology

Decreased lymphatic HIF-2α accentuates lymphatic remodeling in lymphedema

Abstract

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 α (HIF-1α), but a reduction of HIF-2α 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 Hif2α exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif2α caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2α is an important mediator of lymphatic health. HIF-2α promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopoietin-1 (Angpt1) gene therapy. Our study suggests that HIF-2α normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2α pathways in lymphedema could mitigate long-term pathology and disability.

Authors

Xinguo Jiang, Wen Tian, Eric J. Granucci, Allen B. Tu, Dongeon Kim, Petra Dahms, Shravani Pasupneti, Gongyong Peng, Yesl Kim, Amber H. Lim, F. Hernan Espinoza, Matthew Cribb, J. Brandon Dixon, Stanley G. Rockson, Gregg L. Semenza, Mark R. Nicolls

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Figure 7

AdAngpt1 but not AdAngpt2 treatment enhances LEC TIE2 signaling after lymphatic injury.

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AdAngpt1 but not AdAngpt2 treatment enhances LEC TIE2 signaling after ly...
(A) Schematic showing previously reported working model of ANGPT1- or ANGPT2-mediated TIE2 activity in blood vascular endothelial cells. At baseline conditions, both ANGPT1 and ANGPT2 promote TIE2 phosphorylation (denoted by p); in inflammation, shedding of TIE1 ectodomain by TNF-α converts ANGPT2 into a TIE2 antagonist. (B) Representative immunofluorescence staining of TIE2 (green) and LYVE-1 (red) in skin tissues harvested from AdControl-, AdAngpt1-, or AdAngpt2-treated mice with lymphatic surgery. DAPI (blue) stains nucleus. White dashed lines demarcate lymphatics. (C) Quantification of LEC TIE2 intensity comparing groups shown in B (n = 5). (D) Representative immunofluorescence staining of p-TIE2 (green) and LYVE-1 (red) in skin tissues harvested from AdControl-, AdAngpt1-, or AdAngpt2- treated mice subjected to lymphatic surgery. DAPI (blue) stains nucleus. White dashed lines demarcate lymphatics. (E) Quantification of LEC p-TIE2 intensity comparing groups shown in D (n = 5). In C and E, data are presented as mean ± SEM; **P < 0.01; by Kruskal-Wallis test followed by Dunn’s multiple comparisons test. n represents numbers of mice. Scale bars: 60 μm (B and D).