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) tow 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 (C) 2010 Elsevier Inc All rights reserved