Multiparity improves outcomes after cerebral ischemia in female mice despite features of increased metabovascular risk

Abstract

Females show a varying degree of ischemic sensitivity throughout their lifespan, which is not fully explained by hormonal or genetic factors. Epidemiological data suggest that sex-specific life experiences such as pregnancy increase stroke risk. This work evaluated the role of parity on stroke outcome. Age-matched virgin (i.e., nulliparous) and multiparous mice were subjected to 60 min of reversible middle cerebral artery occlusion and evaluated for infarct volume, behavioral recovery, and inflammation. Using an established mating paradigm, fetal microchimeric cells present in maternal mice were also tracked after parturition and stroke. Parity was associated with sedentary behavior, weight gain, and higher triglyceride and cholesterol levels. The multiparous brain exhibited features of immune suppression, with dampened baseline microglial activity. After acute stroke, multiparous mice had smaller infarcts, less glial activation, and less behavioral impairment in the critical recovery window of 72 h. Behavioral recovery was significantly better in multiparous females compared with nulliparous mice 1 mo after stroke. This recovery was accompanied by an increase in poststroke angiogenesis that was correlated with improved performance on sensorimotor and cognitive tests. Multiparous mice had higher levels of VEGF, both at baseline and after stroke. GFP + fetal cells were detected in the blood and migrated to areas of tissue injury where they adopted endothelial morphology 30 d after injury. Reproductive experience has profound and complex effects on neurovascular health and disease. Inclusion of female mice with reproductive experience in preclinical studies may better reflect the life-long patterning of ischemic stroke risk in women.sex differences | multiparity | microglia | ischemic stroke | microchimerism N early 800,000 people in the United States experience a new or recurrent stroke each year, and 55,000 more women than men are affected by stroke (1). Stroke is a sexually dimorphic disease impacted by genetics, hormones, and the environment (2). According to CDC data, 85% of women in the United States have given birth by age 40, whereas the number of lifetime pregnancies per woman varies by race and socioeconomic status. Therefore, child-bearing women represent a significant proportion of the female population, including those at risk for stroke. Moreover, this suggests that a large proportion of the elderly female populationwho is at highest risk for stroke-may be differentially at risk. Epidemiological data suggest that increasing parity is associated with higher risk of cardiovascular disease (CVD) and stroke and late-life vascular comorbidities, including carotid atherosclerosis (3, 4). However, recent reports suggest that parity has a significant protective effect against CVD mortality (5). The effect of parity on outcome following ischemic stroke is yet unresolved.Pregnancy induces profound acute and long-term physiological changes in the body that influence future vascular health through hormonally med...

Shaping Microglial Phenotypes Through Estrogen Receptors: Relevance to Sex-Specific Neuroinflammatory Responses to Brain Injury and Disease

“…The reasons for the lack of effectiveness of minocycline and other drugs in women are not clear. However, cumulative evidence suggests that microglial responses to stroke injury are sex-specific (McCullough et al, 2016), developmentally determined (Villa et al, 2018), modified by age (Yan et al, 2014), and influenced by reproductive experiences such as pregnancy and parity that are unique to women (Ritzel et al, 2017). Because the expression and function of ERs is also developmentally regulated (Perez-Alvarez et al, 2012;Platania et al, 2003;Prewitt and Wilson, 2007;Wilson et al, 2011) and influenced by age (Ianov et al, 2017;Morgan and Finch, 2015;Zuloaga et al, 2014) and sex (Kelly et al, 2013;Waters et al, 2015;Wilson et al, 2011;Zuloaga et al, 2014) it is reasonable to propose that classical and membrane ERs participate in the manifestation of microglial responses to ischemic injury in a sex-and age-specific fashion.…”

Towards an understanding of women's brain aging: the immunology of pregnancy and menopause

“…E2-driven anti-inflammatory effects on microglia activation has also been shown to be dose-dependent [190]. Haim and colleagues reported that microglia density and number was significantly reduced in multiple brain regions in pregnant and postpartum female rats relative to virgin rats [50], and Ritzel and colleagues found that compared to nulliparous mice, parous mice had less reactive microglia [230]. Pregnancy-related alterations in microglia density, number, and activity could contribute to reduced low-grade neuroinflammation later in life, potentially augmenting the capacity for neuroplastic compensation in response to perimenopausal inflammation processes.…”

Impact of Advanced Maternal Age on Physiologic Adaptations to Pregnancy in Vervet Monkeys

“…These data suggest that either AMA disrupts the protective mechanisms afforded by previous pregnancies, or, that after a certain threshold of previous pregnancies the protective mechanism of parity is lost. Parity has also been associated with immunological tolerance to certain infections during pregnancy such as malaria 46–48 and multiparity has been demonstrated to confer immunotolerance in rodent models of stroke 49 , indicating a protective role to maternal health in multiparous mothers. While not tested in the current study, further investigation into AMA primiparous third trimester physiology is warranted to determine if multiparity is protective against the development of clinical preeclampsia.…”