Sphingosine-1-phosphate signaling pathway alteration in brain microvessel of intrauterine growth restricted and preeclamptic mice
Low birth weight or intrauterine growth restriction (IUGR) affects 350,000 infants annually in the United States. The repercussions of in utero growth insufficiency can be observed past infancy. IUGR is associated with increased risk of cerebrovascular disease development in postnatal life, including stroke. This risk may be due to IUGR fetuses adapting their vasculature to conserve oxygen. Preeclampsia, a condition associated with IUGR development, affects 1 in 25 pregnancies annually in the United States. People with preeclampsia are also more likely to experience stroke. The sphingosine-1-phosphate (S1P) pathway is implicated in stroke as its components regulate vascular permeability, vascular integrity, and blood pressure. This study aims to identify possible involvement of the S1P pathway in brain vasculature of IUGR offspring and preeclampsia murine models induced by reduced uterine perfusion (RUP). C57BL/6J female mice underwent RUP or sham surgeries at gestational day 13. Control and IUGR offspring from sham and RUP moms, respectively, at 24 weeks of age were used for brain microvessel extraction. Real time polymerase chain reaction analyzed brain microvessel gene expression for various S1P pathway components including S1P receptors and sphingosine kinases. We found deficient S1PR1, S1PR2, SPHK1, Asah2, and Sgpl1 expression in IUGR offspring. RUP dam mice exhibited decreased SPHK1 and increased Sgpl1 as well as Plpp1 expression. These components mediate vasodilation, vascular permeability, angiogenesis, and recycling and degradation pathways of S1P. This increased risk of stroke may be explained by alterations of S1PR1, S1PR2, SPHK1, Asah2, Sgpl1, Plpp1, and CerS4 due to the S1P pathway's involvement in blood pressure homeostasis and blood vessel integrity.