Brain mitochondrial dysfunction in postpartum preeclamptic rodents

Purpose: Pre-eclampsia (PE), new-onset hypertension during pregnancy, impacts 3-8% of all births in the USA yearly and causes significant neurological damage to the mother during and after pregnancy. Studies show postpartum PE women to have increased risks of hypertension (HTN) and cerebrovascular dysfunction (CVD). Although the cause of HTN and cerebral damage is unknown, mitochondrial dysfunction (mtDys) may play a role. MtDys includes reduced mitochondria-specific antioxidants, raised mitochondrial reactive-oxygen species, changes in mitochondrial fission and fusion proteins, and reduced efficiency of the electron transport chain (ETC). Previous studies in our lab indicate associations between cardiac mtDys and the reduced uterine perfusion pressure (RUPP) rat model of PE with HTN at 10 weeks postpartum (PMID: 34727994). However, cerebral mtDys has not been examined in RUPP rats postpartum. This study aims to examine cerebral mitochondrial functional proteins in hypertensive RUPP postpartum rats at six weeks. We hypothesize that RUPP postpartum rats will have lower amounts of cerebral mitochondrial functional proteins compared to control (CON) postpartum rats. Methods: We divided pregnant Sprague Dawley rats into two groups: CON normal pregnant (NP, n = 4) and RUPP (n = 4). Then, the RUPP surgery was performed on gestational day 14. Pregnant rats gave birth naturally and weaned for three weeks. Six weeks after giving birth, rats were euthanized for brain collections to measure functional proteins via Western Blot analysis, including ETC complexes (Complexes I-V), fusion proteins (OPA-1 and MFN-2), fission protein (DRP-1), and mitochondria-specific antioxidant (MnSOD). Results: In the brain, RUPP postpartum rats have significantly reduced Complex I proteins compared to NP postpartum rats (91 ± 2.27 vs. 100 ± 2.45 IU/protein/CON %, p < 0.05) with slight decreases in Complexes II (93 ± 4.14 % vs. 100 ± 7.57 IU/protein/CON %, ns), III (91 ± 3.18 vs. 100 ± 6.11 IU/protein/CON %, ns), IV (86 ± 11.25 vs. 100 ± 7.95 IU/protein/CON %, ns), and V (92 ± 3.99 vs. 100 ± 6.33 IU/protein/CON %, ns). RUPP and NP postpartum rats have no significant differences in fusion proteins OPA-1 (102 ± 2.56 vs. 100 ± 2.02 IU/protein/CON %, ns) and MFN-2 (106 ± 18.25 vs. 100 ± 14.35 IU/protein/CON %, ns). Fission protein DRP-1 has an increase in RUPP postpartum rats compared to NP postpartum rats (111 ± 6.92 vs. 100 ± 4.55 IU/protein/CON %, ns). RUPP postpartum rats have significantly decreased MnSOD in comparison to NP postpartum rats (89 ± 2.00 vs. 100 ± 2.45 IU/protein/CON %, p < 0.05). Conclusion: RUPP postpartum rats have cerebral mtDys indicated by decreased ETC complexes, especially Complex I. RUPP postpartum rat brains have reduced MnSOD, which suggests elevated mitochondrial oxidative stress. Furthermore, raised mitochondrial fission in the brain supports the presence of mitochondrial damage and mtDys. Future studies will examine the role of cerebral mtDys in causing HTN and CVD in RUPP postpartum rats. This study is clinically relevant because our findings provide a possible mechanism for the pathophysiology of CVD in postpartum PE women and novel targets for cerebral mitochondrial therapy.