Persistent cerebrovascular injury after preeclampsia in the STOX1A mouse model: implications for prokineticin signaling
Preeclampsia (PE) is a pregnancy-related hypertensive disorder associated with neurological complications that may persist beyond pregnancy. Prokineticins (PROK1 and PROK2) and their receptors (PROKR1 and PROKR2) regulate angiogenesis and inflammation and may be involved to PE-associated cerebrovascular injury. This study investigated alterations of the maternal brain prokineticin system during PE and 8 months postpartum, and assessed the consequences of prokineticin receptor inhibition using the PROKR antagonist PC1. Female WT FVB/N mice mated with transgenic males overexpressing STOX1A were used as a model of PE and received PC1 or vehicle during gestation. Circulating and regional brain PROK levels and receptor expression were assessed by ELISA and Western blotting. Long-term cerebral abnormalities were evaluated using high-resolution MRI and GFAP immunostaining. PE mice exhibited hypertension, proteinuria, reduced placental efficiency, and elevated circulating PROK1 and PROK2 levels. PC1 prevented hypertension and attenuated the elevation of circulating PROKs but did not prevent proteinuria or reduced placental efficiency. During PE, hippocampal PROK1 increased while PROK2 decreased; these changes persisted despite treatment. At 7 months postpartum, both PROKs were elevated in the cortex, and these increases were prevented by PC1. Region-specific changes in PROKR1 immunoreactivity and PROKR2 expression showed variable responses to treatment. MRI revealed hippocampal and parieto-temporal T2* hypointensities compatible with microhemorrhagic injury, post-contrast T1 abnormalities supporting blood-brain barrier disruption, and a distinct caudoputamen T1-hyperintense lesion potentially representing a nonhemorrhagic component. PC1 prevented focal cerebral lesions and associated astrocyte reactivity, whereas regional diffusion abnormalities persisted. These findings implicate prokineticin signaling in persistent PE-associated brain injury and support the potential of receptor antagonism to limit selected cerebral alterations.