Decreased lymphatic HIF-2a accentuates lymphatic remodeling in lymphedema

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 a (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 Hif2a exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif2a 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 (Angptl) 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.