| First Author | Jiang X | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 10 | Pages | 5562-5575 |
| PubMed ID | 32673288 | Mgi Jnum | J:302486 |
| Mgi Id | MGI:6508159 | Doi | 10.1172/JCI136164 |
| Citation | Jiang X, et al. (2020) Decreased lymphatic HIF-2alpha accentuates lymphatic remodeling in lymphedema. J Clin Invest 130(10):5562-5575 |
| abstractText | 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-1alpha), but a reduction of HIF-2alpha 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 Hif2alpha exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif2alpha caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2alpha is an important mediator of lymphatic health. HIF-2alpha 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-2alpha normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2alpha pathways in lymphedema could mitigate long-term pathology and disability. |
