α‐Tocopheryl phosphate—An activated form of vitamin E important for angiogenesis and vasculogenesis?

Abstract

Vitamin E was originally discovered as a dietary factor essential for reproduction in rats. Since then, vitamin E has revealed many important molecular properties such as the scavenging of reactive oxygen and nitrogen species or the modulation of signal transduction and gene expression in antioxidant and nonantioxidant manners. A congenital disease, ataxia with vitamin E deficiency, which is characterized by impaired enrichment of α-tocopherol (αT) in plasma due to mutations in the α-tocopherol transfer protein gene, has been discovered. An effect of vitamin E on angiogenesis and vasculogenesis has been observed in several studies, and recently, it has been demonstrated in the placenta of pregnant ewes, possibly involving the stimulation of vascular endothelial growth factor (VEGF) expression. We recently observed that the phosphorylated form of αT, α-tocopheryl phosphate (αTP), increases the expression of VEGF. We propose that the stimulatory effect of αT on angiogenesis and vasculogenesis is potentiated by phosphorylation to αTP, which may act as a cofactor or active lipid mediator increasing VEGF expression. Increased VEGF expression and consequent enhanced angiogenesis and vasculogenesis induced by αTP may explain not only the essential roles of vitamin E on reproduction, but also its beneficial effects against pre-eclampsia, ischemia/reperfusion injury, and during wound healing. It may also serve as a survival factor for brain and muscle cells. The finding that αTP may regulate vasculogenesis may indicate potential, important pathophysiological implications.

α‐Tocopheryl Phosphate Induces VEGF Expression via CD36/PI3Kγ in THP‐1 Monocytes

“…In fact, we find that αT, and more so αTP, γTP, and EPC‐K1 all activate HIF1α and CREB activity, and since over‐expression of PI3Kγ and Akt also stimulated it, VEGF is most likely activated via a PI3Kγ/Akt‐mediated increase of CREB and HIF1α activity. In line with that, HIF1α has been reported to be regulated by vitamin E leading to the induction of the VEGF promoter (reviewed in [Zingg et al, ]). For EPC‐K1, the effects on VEGF, CREB‐RE, and HRE can be explained as result of hydrolysis to αTP after internalization by CD36 [Ohba et al, ], or it may act as an intact molecule within these pathways (reviewed in [Munteanu and Zingg, ; Zingg et al, ]).…”

Modulation of Phosphorylation of Tocopherol and Phosphatidylinositol by hTAP1/SEC14L2-Mediated Lipid Exchange

“…during post-infarction wound healing [64] or during development acting as tubulogenic morphogen during vasculo- and/or nephro-genesis [65]. Whether activation of PI3K/Akt/VEGF and angiogenesis/vasculogenesis by αTP mediates the essential function of αT to prevent fetal resorption and ischemia/reperfusion injury in placenta, embryo, brain and muscle remains to be further investigated [66]. It appears possible that usage of αT/αTP-induced PI3Kγ-mediated signalling to enhance angiogenesis e.g.…”

Micronutrient deficiencies in pregnancy worldwide: health effects and prevention

“…46 The placenta expresses vitamin D receptors and can convert 25-hydroxyvitamin D [25(OH)D] to active calcitriol — which is probably utilized for localized paracrine/autocrine functions as calcitriol is not transferred to the fetus. 47 Vitamin D promotes placental VEGF production, 48 modulates immune function, 49,50 and is thought to support implantation and placental metabolism, 47 providing plausible mechanisms for positive associations between vitamin D status birth outcomes.…”

“…45, 61 Other water soluble vitamins (such as, vitamins B 6 , B 12 and C) are also actively transported to the fetus, 64 while fat-soluble vitamins tend to cross the placenta along a gradient that parallels maternal status. 46, 65, 66 …”