Low vitamin C and increased oxidative stress and cell death in mice that lack the sodium-dependent vitamin C transporter SVCT2

Abstract

The sodium-dependent vitamin C transporter (SVCT2) is responsible for the transport of vitamin C into cells in multiple organs, from either the blood or the cerebrospinal fluid. Mice null for SVCT2 (SVCT2 −/−) do not survive past birth but the cause of death has not yet been ascertained. After mating of SVCT2 +/− males and SVCT2 +/− females, fewer SVCT2 −/− and SVCT2 +/− progeny were observed than would be expected according to Mendelian ratios. Vitamin C levels in SVCT2 −/−, SVCT2 +/−, and SVCT2 +/+ were genotype-dependent. SVCT2 −/− fetuses had significantly lower vitamin C levels than littermates in placenta, cortex, and lung, but not in liver (the site of vitamin C synthesis). Low vitamin C levels in placenta and cortex were associated with elevations in several markers of oxidative stress: malondialdehyde, isoketals, F 2-isoprostanes, and F 4-neuroprostanes. Oxidative stress was not elevated in fetal SVCT2 −/− lung tissue despite low vitamin C levels. In addition to the expected severe hemorrhage in cortex, we also found hemorrhage in the brain stem, which was accompanied by cell loss. We found evidence of increased apoptosis in SVCT2 −/− mice and disruption of the basement membrane in fetal brain. Together these data show that SVCT2 is critical for maintaining vitamin C levels in fetal and placental tissues and that the lack of SVCT2, and the resulting low vitamin C levels, results in fetal death and, in SVCT2 −/− mice that survive the gestation period, in oxidative stress and cell death.