Decreased lymphatic HIF-2a accentuates lymphatic remodeling in lymphedema. The Journal of clinical investigation Jiang, X. n., Tian, W. n., Granucci, E. J., Tu, A. B., Kim, D. n., Dahms, P. n., Pasupneti, S. n., Peng, G. n., Kim, Y. n., Lim, A. H., Espinoza, F. H., Cribb, M. n., Dixon, J. B., Rockson, S. G., Semenza, G. L., Nicolls, M. R. 2020


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 (HIF)-1a, but a reduction of HIF-2a 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 Hif-2a exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif-2a caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2a is an important mediator of lymphatic health. HIF-2a 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-2a normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2a pathways in lymphedema could mitigate long-term pathology and disability.

View details for DOI 10.1172/JCI136164

View details for PubMedID 32673288