We appreciate the comments of Dr Das regarding our recent article. The roles of angiogenic factors, endothelial and constitutive nitric oxide (NO) synthase (NOS), NO, and vascular endothelial growth factor in placental development/function with respect to intrauterine growth restriction (IUGR) are well recognized. Proper placental development depends on the regulated expression of both angiogenic promoting and inhibitory factors. While little is known regarding the effect of magnesium (Mg) on angiogenic factors, endothelial cell proliferation and migration (key components of angiogenesis) are regulated by Mg. In addition, endothelial NOS, constitutive NOS, NO, and vascular endothelial growth factor are mediators of vasodilation. Although the bilateral artery ligation model employed in our study has not been associated with dysfunctional placental angiogenesis, it would be of interest to examine the effect of Mg on mediators of vasodilation.

It can be postulated that both extracellular and intracellular magnesium [Mg ²⁺ ]i affect cellular processes that regulate proliferation and migration, as well as inflammation and angiogenesis. Extracellular Mg ²⁺ antagonizes calcium 2+ influx into smooth muscle cells promoting vasodilatation, in part, via NO/NOS. [Mg ²⁺ ]i functions as an intracellular signaling messenger. Thus, exploring the potential role of [Mg ²⁺ ]i as a second messenger within the fetal-placental unit during IUGR is clearly warranted.

Finally, as suggested by Dr Das, the link between Mg deficiency and fatty acids is another important perspective to consider. We have investigated the effect of Mg deficiency and supplementation on cholesterol and triglyceride-fatty acid profiles in pregnant rats. While we did not observe significant differences in total cholesterol or triglycerides levels, Mg deficiency was accompanied by a significant reduction in maternal plasma polyunsaturated fatty acid (PUFA) levels (20:3ω6, 20:4, 20:5, 22:5ω3, 22:6, P < .05, unpublished data). By contrast, Mg-supplemented dams exhibited a 2-fold increase in plasma 20:5 levels vs controls ( P < .05, unpublished data). We did not evaluate fatty acid profiles in our study, as we did not expect significant changes within 24 hours. Interestingly, Mg status is also linked to the synthesis of arachidonic acid (20:4)-derived thromboxane A(2), a proinflammatory eicosanoid and known inducer of IUGR. ω-3 PUFAs can reduce the expression of proinflammatory factors (eg, interleukin [IL]-6, IL-1 receptor agonist, tumor necrosis factor-α, and C-reactive protein) and promote the expression of antiinflammatory factors (eg, soluble IL-6r, IL-10, transforming growth factor-β). In addition, ω-3 PUFAs give rise to resolvins and protectins, antiinflammatory lipid mediators ; these lipid mediators have not been examined in IUGR. Active research in our laboratory focuses on better understanding Mg-mediated fetal protective effects.