Vitamin D mitigates soluble endoglin levels in preeclampsia by regulating sphingomyelin/ ceramide content of the placental exosome

Vitamin D deficiency is associated with increased risk of preeclampsia. Vitamin D influences angiogenesis in preeclampsia, however the underlying mechanism remains unclear. Placental exosomes are released in the maternal circulation as early as the 6th week of gestation and its levels are reported to be increased in preeclampsia. Similarly, changes in the placental exosome cargo (increased sphingomyelin (SM) content) has also been reported in women with preeclampsia. Endoglin, an anti-angiogenic marker, has an affinity for SM-18:0 enriched microdomains which when released into the maternal circulation may lead to endothelial dysfunction. Our earlier studies in preeclampsia reports that alterations in the levels of angiogenic markers predate clinical diagnosis of preeclampsia. We have also reported that maternal vitamin D status influence fatty acid levels and their metabolism. It has been reported that vitamin D influences sphingolipid metabolism pathway and increases ceramide levels in the exosome bilayer. It is likely that vitamin D levels influence sphingomyelinase activity thereby affecting composition of sphingolipids and ceramides in exosomes and their release into the maternal circulation. Since, SM-18:0-enriched exosomes are associated with increased endoglin levels (in the exosomal cargo); it is possible that vitamin D influences angiogenesis by regulating the content of lipids in exosomes. We hypothesize that lower maternal vitamin D levels will increase sphingomyelin content in the exosomal bilayer resulting in increased endoglin cargo in the placental exosome which will be released into the maternal circulation. This will subsequently lead to impaired angiogenesis and endothelial dysfunction in preeclampsia.