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Decreased lymphatic HIF-2[alpha] accentuates lymphatic remodeling in lymphedema
- Source :
- Journal of Clinical Investigation. October, 2020, Vol. 130 Issue 10, p5562, 14 p.
- Publication Year :
- 2020
-
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.<br />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 [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 130
- Issue :
- 10
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.637941308
- Full Text :
- https://doi.org/10.1172/JCI136164