Decreased Lymphatic Hif-2 Alpha Accentuates Lymphatic Remodeling In Lymphedema
JOURNAL OF CLINICAL INVESTIGATION(2020)
摘要
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-7 (Angpt1) 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.
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关键词
Inflammation,Lymph,Vascular Biology,endothelial cells,hypoxia
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