| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
During embryonic lymphatic development, a homeobox transcription factor Prox1 plays important roles in sprouting and migration of a subpopulation of blood vessel endothelial cells (BECs) towards VEGF-C expressing cells. However, effects of Prox1 on endothelial cellular behavior remain to be elucidated. Here we show that Prox1, via induction of integrin α9 expression, inhibits sheet formation and stimulates motility of endothelial cells (mouse embryonic stem cell-derived endothelial cells and human umbilical venous endothelial cells : HUVECs). Prox1-expressing BECs preferentially migrated toward VEGF-C and PDGF-BB up-regulation of the expression of integrin α9 and VEGF receptor 3 (VEGFR3), and that of PDGF receptor β (PDGFRβ), respectively. In mouse embryos, expression of VEGFR3 and integrin α9 is increased in Prox1-expressing lymphatic endothelial cells (LECs) compared to BECs. Knockdown of Prox1 expression in human LECs led to decrease in the expression of integrin α9, VEGFR3 and PDGFRβ, resulting in the decreased chemotaxes toward VEGF-C and PDGF-BB. These findings suggest that Prox1 plays important roles in conferring and maintaining the characteristics of LECs by modulating multiple signaling cascades, and that integrin α9 may function as a key regulator of lymphangiogenesis acting downstream of Prox1.
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