1. Decreased lymphatic HIF-2[alpha] accentuates lymphatic remodeling in lymphedema
- Author
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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., and Nicolls, Mark R.
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Lymphedema -- Development and progression ,Health care industry ,Stanford University. School of Medicine - 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[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., Introduction Lymphedema is characterized by a chronic state of lymphatic vascular insufficiency with interstitial edema, inflammation, and dermal pathology; it affects 100-250 million individuals globally, but lacks effective pharmacological therapies [...]
- Published
- 2020
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