Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 28, Issue 4, Pages 658-664Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.107.150433
Keywords
VEGF-A; VEGFR1; lymphangiogenesis
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Objective - Angiogenesis and lymphangiogenesis are complex phenomena that involve the interplay of several growth factors and receptors. Recently, we have demonstrated that in Keratin-14 (K14) promoter-driven Vegf-A transgenic (Tg) mice, not only angiogenesis but also lymphangiogenesis is stimulated. However, the mechanism by which VEGFR1 is involved in lymphangiogenesis remains unclear. Methods and Results - To examine how important the tyrosine kinase (TK) of VEGFR1 is in lymphangiogenesis in K14 Vegf-A Tg mice, we crossed the K14 Vegf-A Tg mice with Vegfr1-tk- deficient mice to generate double mutant K14 Vegf-A Tg Vegfr1 tk(-/-) mice. K14 Vegf-A Tg Vegfr1 tk(-/-) mice exhibit a remarkable decrease in lymphangiogensis as well as angiogenesis in subcutaneous tissues. To address the mechanism underlying the decrease in lymphangiogensis, we investigated the recruitment of monocyte-macrophage-lineage cells into the skin. The recruitment of VEGFR1-expressing macrophages driven by VEGF-A was reduced in K14 Vegf-A Tg Vegfr1 tk(-/-) mice. Vegf-A Tg mice that received Vegfr1-tk- deficient bone marrow showed a reduction of macrophage recruitment, lymphangiogenesis and angiogenesis compared with those in K14 Vegf-A Tg mice. Conclusions - VEGFR1 signaling promotes lymphangiogenesis as well as angiogenesis mainly by increasing bone marrow - derived macrophage recruitment.
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