Decreased lymphatic HIF-2? accentuates lymphatic remodeling in lymphedema.

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 ? (HIF-1?), but a reduction of HIF-2? 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? exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif2? caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2? is an important mediator of lymphatic health. HIF-2? 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-2? normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2? pathways in lymphedema could mitigate long-term pathology and disability.

SUBMITTER: Jiang X 

PROVIDER: S-EPMC7524470 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature