<h5>Introduction</h5>
HIF-1a is a key regulator of angiogenesis with a suggested role in lymphangiogenesis. We have previously demonstrated that hypoxia results in an HIF-1a dependent increase in VEGF-C and lymphatic differentiation in vitro. This study used a model of surgical lymphedema to further investigate the role of HIF-1a in the regulation of lymphangiogenesis in vivo.</P><h5>Methods</h5>
We utilized a mouse tail model of lymphatic regeneration in which superficial and deep lymphatics are excised microsurgically. Post-operatively, mice were administered YC1, a small molecule inhibitor of HIF-1a. Lymphangiogenesis was evaluated and correlated with expression patterns of VEGF-A and VEGF-C. Transgenic mice expressing a luciferase-HIF-1a fusion protein, as well as western blot analysis, were used to localize patterns of HIF-1a, VEGF-C, and VEGF-A expression at various times after surgery. The role of tissue hypoxia in HIF-1a regulation was characterized by pimonidazole staining.</P><h5>Results</h5>
Inhibition of HIF-1a delayed lymphangiogenesis as evidenced by increased tail lymphedema (4-fold), dilated lymphatics (4-fold), impaired lymphatic fluid flow, and down-regulation of lymphatic differentiation markers (p<0.01). Impaired lymphangiogenesis was associated with significantly decreased tissue expression of VEGF-A and VEGF-C protein and mRNA (50% reduction, p<0.01). Sustained HIF-1a expression across the wound correlated with a gradient of hypoxia as assessed by western blot and pimonidazole staining.</P><h5>Conclusions</h5>
This study provides evidence that HIF-1a directly regulates lymphangiogenesis through modulation of VEGF-C and VEGF-A in vivo. These findings thus suggest a means to regulate lymphangiogenesis during metastases or wound healing.</P>
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HIF-1a regulates VEGF-C expression and is required for lymphangiogenesis
Zampell, Jamie C.; Daluvoy, Sanjay; Avraham, Tomer; Yan, Alan; Kueberuwa, Essie; Mehrara, Babak J.
Follow Journal of the American College of Surgeons
, Volume 211 (3)
Elsevier – Sep 1, 2010
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