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

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, F2-isoprostanes, and F4-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.