Induction of VEGF expression in monocytes by alpha‐tocopherol and alpha‐tocopheryl phosphate via PI3Kgamma/Akt and hTAP1/SEC14L2‐mediated lipid exchange (1000.1)

Abstract

In several studies, vitamin E has been observed to influence angiogenesis and vasculogenesis. We recently observed that the phosphorylated form of α‐tocopherol (αT), α‐tocopheryl phosphate (αTP), increases the expression of the vascular endothelial growth factor (VEGF), which may stimulate angiogenesis and vasculogenesis and enhance the survival of cells. Here we investigated the molecular signaling mechanisms by which αTP induces VEGF expression using cultured THP‐1 monocytes and HEK293 cells as model systems. αT and more so αTP increased VEGF‐promoter activity in a phosphatidylinositol‐3‐kinase gamma (PI3Kγ) ‐dependent manner. In contrast, after over‐expression of PI3Kγ and/or Akt, VEGF promoter activity is inhibited by αT and more so by αTP. PI3Kγ‐induced VEGF expression was reduced when the human tocopherol associated protein 1 (hTAP1/SEC14L2) was over‐expressed, that could be reverted by αT and more so by αTP. Recombinant hTAP1/hSEC14L2 binds both αT and αTP and reduces the in vitro activity of the PI3Kγ most likely by forming a stalled/inactive hTAP1/PI3Kγ heterodimer. The addition αT, βT, γT, δT or αTP differentially stimulates PI3Kγ. We suggest a novel signaling mechanism by which αT or αTP stimulate PI3Kγ activity by facilitating egress and presentation of sequestered PI from hTAP1 to the enzyme and/or dissociating the inactive heterodimer. Supported by USDA Contract #58‐1950‐0‐014.Grant Funding Source: Supported by USDA Contract #58‐1950‐0‐014