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 Article has an altmetric score of 13

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 11

Schematic diagram showing LEC HIF-2α promotes lymphedema resolution by regulating TIE2 signaling.

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Schematic diagram showing LEC HIF-2α promotes lymphedema resolution by r...
Lymphatic injury-caused edema and inflammation lead to reduced LEC HIF-2α expression, decreased tissue ANGPT1, increased ANGPT2 and TNF-α, and lower TIE1 expression (attributable to TNF-α–mediated ectodomain shedding). These changes collectively suppress LEC TIE2 activity and reduce the expression of the adherens junctional protein VE-Cadherin. Reduction of VE-Cadherin compromises lymphatic function, as evidenced by reduced interstitial drainage and increased lymphatic leakage, which exacerbates tissue edema and inflammation. When LEC HIF-2α is overexpressed, TIE2 and p-TIE2 expression increase, and lymphatic function, tissue inflammation, and edema improve. This resolution is accompanied by ANGPT1 restoration, declined TNF-α–mediated TIE1 shedding, and a possible agonistic switch wherein ANGPT2 strengthens LEC TIE2 signaling.