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 3

LEC Hif2α-KO augments tissue swelling and cutaneous skin thickness and exacerbates lymphatic malfunctioning.

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LEC Hif2α-KO augments tissue swelling and cutaneous skin thickness and e...
(A) Serial measurements of tail volume in WT and LEC Hif2a-KO mice with sham (n = 6) or lymphatic surgery (n = 8). L, lymphedema; S, sham. (B) Representative images of WT or LEC Hif2α-KO mouse tail 24d following lymphatic surgery. (C) Representative H&E staining of mouse-tail samples of WT or LEC Hif2α-KO mice subjected to lymphatic surgery. Black arrows point to dilated lymphatic vessels; double-headed black arrows illustrate the cutaneous thickness. (D and E) Quantification of cutaneous thickness (D) and lymphatic area (E) comparing groups shown in C (n = 4–5). (F) Representative NIR imaging of tails of WT and LEC Hif2α-KO mice after lymphatic surgery. Leaked NIR dye, IRDye 800CWNHS ester, was measured 3 minutes after injection. Two separate images were taken for the tail segment between the injection and surgical sites, and stitched for data presentation. Retained NIR dye was measured 60 minutes after injection. Red arrows point to interstitial area with dye leakage, white arrows point to surgical sites. (G and H) Quantification of the leaked (G) and retained (H) NIR dye intensity comparing the groups shown in F (n = 5). In A, D, E, G, and H, data are presented as mean ± SEM; *P < 0.05; **P < 0.01; by the Mann-Whitney test. n represents numbers of mice. Scale bar: 500 μm (C).