Sex differences in cerebrovascular dysfunction and hypertension in offspring of hypertensive pregnant rats

PURPOSE: Offspring from preeclamptic women have a greater risk of hypertension and cerebrovascular dysfunction later in life. One of the major contributors of cerebrovascular dysfunction is impaired cerebral blood flow (CBF) autoregulation. In the USA, 1 in 25 pregnancies are preeclamptic. Preeclampsia, as defined as new-onset hypertension during pregnancy, is an inflammatory condition characterized by elevated interleukin 17 (IL-17), mitochondrial reactive oxygen species (mtROS), mitochondrial dysfunction (mt-Dys), and intrauterine growth restriction (IUGR). Preliminary work from our laboratory demonstrates that offspring from preeclamptic rats have sex differences. Males have hypertension and a greater impairment of CBF autoregulation, while females have no change in blood pressure with impaired CBF autoregulation. The exact mechanisms for the sex differences in cerebrovascular dysfunction and hypertension is unknown and is the focus of this study. We hypothesize that changes in cerebral mt-dys, cerebral mtROS, and circulating IL-17 contributes to the sex differences in hypertension and cerebrovascular dysfunction in male and female offspring from preeclamptic rats. METHODS: In this study, we compared male and female offspring from normal pregnant and preeclamptic Sprague Dawley rats. All offspring were divided into controls (CON) and IUGR by sex. Hypertensive male and non-hypertensive female offspring's with impaired CBF autoregulation were examined at 17 weeks of age for changes in cerebral mitochondrial electron transport chain (ETC) protein complexes, cerebral manganese superoxide dismutase (MnSOD), and circulating IL-17. RESULTS: Female CON (151±5% IU/Protein/male CON) and IUGR (149±8 %IU/Protein/male CON) offspring have increased MnSOD compared to CON (100±7 %IU/Protein/male CON) and IUGR (122±4 %IU/Protein/male CON) males (p< 0.05). No changes in female ETC protein complexes between IUGR and CON. Male IUGR have a decrease in complex II (71±5 vs. 100±8 %IU/Protein/male CON, p< 0.05) and V (57±2 vs. 100±10 %IU/Protein/male CON, p< 0.05) ETC proteins, and elevated IL-17 (944±370 vs. 412±115 pg/mL, ns) compared to CON males. CONCLUSION: Male IUGR offspring have mt-Dys and elevated IL-17, which may contribute to hypertension and a greater impairment in CBF autoregulation. Female IUGR offspring may be protected due to an increase in mitochondrial antioxidants. In summary, studying the dimorphic sex differences in the mechanisms of hypertension and cerebrovascular dysfunction in offspring of preeclamptic women, may improve the offspring's risk of hypertension, cardiovascular disease, stroke, and cognitive dysfunction later in life.