Abstract
In 1983, three of us reported in “Science” that umbilical-placental arteries and veins, obtained from normal pregnant women at term delivery, when exposed in vitro to low concentrations of Mg2+ went into vasospasm; the lower the Mg2+, the greater the contractile force developed. These blood vessels also demonstrated amplified contractile force development when challenged with circulating amines and peptides (e.g., norepinephrine, 5-HT, angiotensin II, etc.). We suggested that severe Mg deficiency during pregnancy could in part be responsible for spontaneous abortions, loss of fetuses, stillbirths, and developmental alterations in infants. Using short-term dietary Mg deficient animals, we have noted a great many molecular and biochemical alterations in ventricular, atrial and somatic vascular smooth muscle alterations including DNA methylation and histone changes leading us to speculate that Mg deficiency may represent a genotoxin promoting mutations and causing epigenetic changes. Over the last 35 years, we have new data on severely preeclamptic and gestational diabetic pregnant women that gives credence to our original hypothesis and demonstrates that recently- discovered developmental proteins, originally found 100 years ago in Drosophila fruit flies termed the “Notch pathway”, due to effects on its wings, appears to be important in development of the umbilical-placental blood vessels in pregnant women. Along with the developmental molecule, p53, these Notch proteins clearly alter the behavior of the umbilical-placental vessels. We believe these new findings probably help to explain many of the genetic-toxicity effects seen in women later in life who develop strokes and cardiovascular diseases. Notch alterations could also play an important role in babies born with cardiac defects.
Highlights
Mutations in pregnant women and fetuses, in early embryonic development of genes, may cause several genetic disorders, spontaneous abortions, and loss of babies
When these new human data are viewed in terms of the results showing damaged DNA and elevated levels of 4-NHE in the vascular smooth muscle cells (VSMc), we believe it becomes very difficult, if not impossible, not to conclude that Mg deficiency plays a role in gestational diabetes and pre-eclampsia-eclampsia in pregnant women
We believe our data, on the cytokine and chemokine levels in Mg-deficient endothelial and vascular smooth muscle cells, obtained from severely pre-eclamptic women, and those with gestational diabetes [31], clearly reinforce our hypothesis that Mg deficiency during pregnancy must be taken into consideration in the etiology of severe pre-eclampsia, gestational diabetes, loss of fetuses, growth retardation, and stillbirth, as three of us suggested almost 40 years ago
Summary
Mutations in pregnant women and fetuses, in early embryonic development of genes, may cause several genetic disorders, spontaneous abortions, and loss of babies. More than 15 years ago, four of us working with primary cultured cerebral vascular smooth muscle cells, we noted that low [Mg2+ ]0 levels resulted in rapid increased formation of MDA [29,33,37] This formation of MDA was found in diverse cardiovascular tissues extracted from rats subjected to 21 days of Mg deficiency [33] as well as in umbilicalplacental VSMc obtained from pregnant women at term pregnancy who had gestational diabetes or eclampsia [38]. We believe these data, when taken together, provide presumptive evidence for our hypothesis that Mg deficiency during pregnancy acts as a genotoxin. Methodology can be found in ref. [41]
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