Preeclampsia history and postpartum risk of cerebrovascular disease and cognitive impairment: Potential mechanisms

Hypertensive disorders of pregnancy such as preeclampsia, eclampsia, superimposed preeclampsia, and gestational hypertension are major causes of fetal and maternal morbidity and mortality. Women with a history of hypertensive pregnancy disorders have increased risk of stroke and cognitive impairments later in life. Moreover, women with a history of preeclampsia have increased risk of mortality from diseases including stroke, Alzheimer’s disease, and cardiovascular disease. The underlying pathophysiological mechanisms are currently not fully known. Here, we present clinical, epidemiological, and preclinical studies focused on evaluating the long-term cerebrovascular and cognitive dysfunction that affect women with a history of hypertensive pregnancy disorders and discuss potential underlying pathophysiological mechanisms

The Endothelin Type A Receptor as a Potential Therapeutic Target in Preeclampsia

Preeclampsia (PE) is a disorder of pregnancy typically characterized by new onset hypertension after gestational week 20 and proteinuria. Although PE is one of the leading causes of maternal and perinatal morbidity and death worldwide, the mechanisms of the pathogenesis of the disease remain unclear and treatment options are limited. However, there is increasing evidence to suggest that endothelin-1 (ET-1) plays a critical role in the pathophysiology of PE. Multiple studies report that ET-1 is increased in PE and some studies report a positive correlation between ET-1 and the severity of symptoms. A number of experimental models of PE are also associated with elevated tissue levels of prepro ET-1 mRNA. Moreover, experimental models of PE (placental ischemia, sFlt-1 infusion, Tumor necrosis factor (TNF) -α infusion, and Angiotensin II type 1 receptor autoantibody (AT1-AA) infusion) have proven to be susceptible to Endothelin Type A (ETA) receptor antagonism. While the results are promising, further work is needed to determine whether ET antagonists could provide an effective therapy for the management of preeclampsia

Whole Brain Radiation-Induced Impairments in Learning and Memory Are Time-Sensitive and Reversible by Systemic Hypoxia

Whole brain radiation therapy (WBRT) is commonly used for treatment of primary and metastatic brain tumors; however, cognitive impairment occurs in 40–50 % of brain tumor survivors. The etiology of the cognitive impairment following WBRT remains elusive. We recently reported that radiation-induced cerebrovascular rarefaction within hippocampal subregions could be completely reversed by systemic hypoxia. However, the effects of this intervention on learning and memory have not been reported. In this study, we assessed the time-course for WBRT-induced impairments in contextual and spatial learning and the capacity of systemic hypoxia to reverse WBRT-induced deficits in spatial memory. A clinical fractionated series of 4.5Gy WBRT was administered to mice twice weekly for 4 weeks, and after various periods of recovery, behavioral analyses were performed. To study the effects of systemic hypoxia, mice were subjected to 11 % (hypoxia) or 21 % oxygen (normoxia) for 28 days, initiated 1 month after the completion of WBRT. Our results indicate that WBRT induces a transient deficit in contextual learning, disruption of working memory, and progressive impairment of spatial learning. Additionally, systemic hypoxia completely reversed WBRT-induced impairments in learning and these behavioral effects as well as increased vessel density persisted for at least 2 months following hypoxia treatment. Our results provide critical support for the hypothesis that cerebrovascular rarefaction is a key component of cognitive impairment post-WBRT and indicate tha

Retinal Venule Coverage by Pericytes Decreases in Multiparous Mice in a Time-Dependent Manner Post-Delivery

Structural changes in the retinal vasculature have been linked to increased cardiovascular risks and also change as a function of age. Because multiparity has been associated with poorer cardiovascular health scores, we hypothesized that changes in retinal vascular caliber would be observed in multiparous, compared to nulliparous, females and retired breeder males. Age-matched nulliparous (n = 6) and multiparous (n = 11, retired breeder females with 4 ± 1 litters), and male breeder (n = 7) SMA-GFP reporter mice were included for assessment of retinal vascular structure. Multiparous females had higher body mass, heart weight, and kidney weight compared to nulliparous mice, with lower kidney and higher brain weight compared to male breeders. There was no difference in number of retinal arterioles or venules, or arteriole or venule diameter among groups; however, venous pericyte density (number per venule area) decreased in multiparous vs. nulliparous mice and was negatively associated with the time since last litter and with age. Our results suggest that the time elapsed since delivery is an important factor to be considered in multiparity studies. Taken together, changes in vascular structure and potentially function, are time- and age-dependent. Ongoing and future work will determine whether structural changes are associated with functional consequences at the blood–retinal barrier

Changes in hippocampal vascular density after re-exposure to ambient oxygen levels.

<p>(A) Representative images of vascular density in the mouse hippocampus. Images were captured using fluorescence microscope at 10× magnification. Scale bar represents 100 µm. (B) Quantification of vascular density (length of vessels per area of tissue). Data represent Mean ± SEM. *p<0.05 vs. Control Normoxic and ^##p<0.01 vs. Radiated Normoxic. N = 5–6 animals per group/treatment.</p

Working memory deficits are evident in radiated mice 4 months post-WBRT.

<p>(A) Schematic of the experimental design used. Impairments in learning occur in the radiated group as measured by: (B) primary errors and (C) primary latency over blocks of trials. Performance during individual trials is shown in (D) as primary errors and (E) as primary latency. Data represent Mean ± SEM. **p<0.00625 vs. Control. N = 9 animals per group.</p