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 4

Deletion of lymphatic endothelial Hif2α impairs dermal lymphatic development and causes adult lymphatic abnormalities.

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Deletion of lymphatic endothelial Hif2α impairs dermal lymphatic develop...
(A) Experimental strategy for assessing the role of deleting LEC Hif2α in embryonic lymphatic development. (B) Location of the dorsal skin harvested. (C) Cartoon diagram of growth of lymphatics in the embryonic dorsal skin. (D) Bright field images of E16.5 control or LEC Hif2α-KO embryos. White arrow denotes lymphedema. (E) Representative E16.5 embryonic dorsal skin lymphatics stained by VEGFR3. Double arrow heads denote the distance between the leading fronts of lymphatic vessels. (F) Quantification of relative distance to closure and relative lymphatic length comparing groups shown in E (n = 5). (G) Representative photographs of ears at 0 and 24 hours after injection of Evans blue dye into control or LEC Hif2α-KO ears 21 days after tamoxifen administration. White dots denote injection sites. The white arrow points to retrograde lymph flow, red arrows point to areas with lymphatic leakage. (H) Extravasated dye was measured via absorbance at 620 nm, relative intensity of retained Evans blue was then calculated (n = 4). F and H, data are presented as mean ± SEM; *P < 0.05; **P < 0.01; by the Mann-Whitney test. n in F represents numbers of embryos from 2 litters, n in H represents numbers of mice. Scale bars: 2 mm (D) and 200 μm (E).