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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:915.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Role of the Low-Affinity Leukotriene B₄ Receptor BLT2 in VEGF-Induced Angiogenesis

Geun-Young Kim; Jin-Wook Lee; Sung-Hoon Cho; Ji-Min Seo; Jae-Hong Kim

From the College of Life Sciences and Biotechnology, Korea University, Seoul.

Correspondence to Jae-Hong Kim, College of Life Sciences and Biotechnology, Korea University, 5-1 Anam-dong, Sungbuk-gu, Seoul, 136-701, Korea. E-mail jhongkim{at}korea.ac.kr

Objective— The leukotriene B₄ (LTB₄) receptor BLT2 is expressed in endothelium, but no clear physiological function for it has yet been identified, especially in vascular angiogenesis. The purpose of this study is to characterize the potential function of BLT2 in vascular endothelial growth factor (VEGF)-induced angiogenesis.

Methods and Results— VEGF significantly upregulates BLT2 expression in human umbilical vein endothelial cells (HUVECs), and BLT2 knockdown by siRNA or inhibition of BLT2 by a specific BLT2 antagonist LY255283 attenuates VEGF-induced angiogenesis, which was determined by its effect on the formation of tube-like structures and on transmigration. The role of BLT2 in VEGF-induced angiogenesis was more evident in vivo, where BLT2 inhibition by LY255283 almost completely blocked VEGF-induced vessel formation in Matrigel-plug assays. In addition, we found that VEGF upregulates synthesis of the BLT2 ligand, 12(S)-hydroxyeicosatetraenoic acid (HETE). siRNA knockdown of 12-lipoxygenase (12-LO) expression attenuates VEGF-induced angiogenesis in HUVECs, and the addition of 12(S)-HETE to the 12-LO knockdown-HUVECs restores VEGF-induced angiogenesis. The activation of BLT2 itself by either 12(S)-HETE or LTB₄ evoked significant angiogenic phenotypes, both in vitro and in vivo.

Conclusion— Our findings indicate that BLT2 plays an essential role in mediating VEGF-induced angiogenesis.

We showed that BLT2 expression in endothelium is highly induced by VEGF, and this induced BLT2 plays a critical role in mediating VEGF-induced angiogenesis. In addition, VEGF-induced angiogenesis in vivo is strictly dependent on BLT2. These data suggest the upregulation of BLT2 may be an important mechanism for VEGF-induced angiogenesis.

Key Words: angiogenesis • VEGF • BLT2 • 12(S)-HETE • 12-lipoxygenase