Induction of VEGF expression by alpha-tocopherol and alpha-tocopheryl phosphate via PI3Kgamma/PKB and hTAP1/SEC14L2-mediated lipid exchange

Authors: ZINGG, JEAN-MARC - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; AZZI, ANGELO - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MEYDANI, MOHSEN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Cellular Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/26/2014
Publication Date: 10/7/2014
Citation: Zingg, J., Azzi, A., Meydani, M. 2014. Induction of VEGF expression by alpha-tocopherol and alpha-tocopheryl phosphate via PI3Kgamma/PKB and hTAP1/SEC14L2-mediated lipid exchange. Journal of Cellular Biochemistry. 116:398-407. https://doi.org/10.1002/jcb.24988.

Interpretive Summary: Vitamin E was initially discovered as a dietary component necessary for reproduction in rats. It has been determined that vitamin E influences the processes known as angiogenesis (the formation of new blood vessels from existing blood vessels) and vasculogenesis (the formation of blood vessels where no pre-existing blood vessels exist.) One form of vitamin E called alpha-tocopheryl phosphate, or alphaTP, has been observed to affect a growth factor specific to cells of the vascular system called the vascular endothelial growth factor (VEGF.) VEGF is important since it promotes angiogenesis and facilitates the formation of new blood vessels during the development of the embryo and the placenta as well as during wound healing. The scientific question was to discover whether the use of vitamin E phosphate (alphaTP) and its effect on tissue and organs can be proved by cell and molecular evidence. We analyzed in detail the signaling mechanism by which alphaTP (vitamin E phosphate) induces production of VEGF. alphaTP was found to activate cell and molecular process that lead to the production of VEGF and is therefore potentially useful in wound healing. Understanding the mechanism that modulates VEGF expression in a controlled manner could lead to applications that support wound healing, prevent ischemia (loss of blood supply to the brain, heart, organs and tissues,) and regulate the formation of blood vessels during reproduction and tumor development. Overall, methods for regulating VEGF would be valuable for their applications to health and medicine, specifically where the body's vascular system is concerned.

Technical Abstract: In several studies, vitamin E has been observed to influence angiogenesis and vasculogenesis. We recently showed that the phosphorylated form of alpha-tocopherol (alphaT), alpha-tocopheryl phosphate (alphaTP), increases the expression of the vascular endothelial growth factor (VEGF). Thus, alphaTP may act as an active lipid mediator increasing VEGF expression, angiogenesis, and vasculogenesis. Here, we investigated the molecular signaling mechanisms by which alphaTP induces VEGF expression using cultured HEK293 cells as model system. alphaT and more so alphaTP increased VEGF-promoter activity in a phosphatidylinositol-3-kinase gamma (PI3Kgamma)-dependent manner. In contrast, after overexpression of PI3Kgamma and/or protein kinase B (PKB), VEGF promoter activity was inhibited by alphaT and more so by alphaTP. Inhibition by alphaT and alphaTP was dependent on the lipid kinase activity of PI3Kgamma, whereas an induction was seen with the protein kinase activity, consistent with a model in which PKB inhibition by alphaT or alphaTP occurs only when activated at the plasma membrane and possibly involves a phosphatase such as PHLPP1. PI3Kgamma-induced VEGF expression was reduced when the human tocopherol-associated protein 1 (hTAP1/SEC14L2) was overexpressed suggesting formation of an inactive PI3Kgamma/hTAP1 heterodimer, that could be reactivated by alphaT and more so by alphaTP. We suggest a novel signaling mechanism by which alphaTP stimulates PI3Kgamma activity by stimulating hTAP-mediated phosphatidylinositol exchange and presentation to the enzyme and/or dissociation of an inactive heterodimer. At cellular level, hTAP may act as sensor for intracellular lipid information (location, type, and amount of lipid) and translate it into responses of PI3K-mediated signaling and gene expression.