Back to Search Start Over

Decreased lymphatic HIF-2[alpha] accentuates lymphatic remodeling in lymphedema

Authors :
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.
Nicolls, Mark R.
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