Abstract
Although epidemiological evidence suggests significant sex and gender-based differences in stroke risk and recovery, females have been widely under-represented in preclinical stroke research. The neurovascular sequelae of brain ischemia in females, in particular, are largely uncertain. We set out to address this gap by a multimodal in vivo study of neurovascular recovery from endothelin-1 model of cortical focal-stroke in sham vs. ovariectomized female rats. Three weeks post ischemic insult, sham operated females recapitulated the phenotype previously reported in male rats in this model, of normalized resting perfusion but sustained peri-lesional cerebrovascular hyperreactivity. In contrast, ovariectomized (Ovx) females showed reduced peri-lesional resting blood flow, and elevated cerebrovascular responsivity to hypercapnia in the peri-lesional and contra-lateral cortices. Electrophysiological recordings showed an attenuation of theta to low-gamma phase-amplitude coupling in the peri-lesional tissue of Ovx animals, despite relative preservation of neuronal power. Further, this chronic stage neuronal network dysfunction was inversely correlated with serum estradiol concentration. Our pioneering data demonstrate dramatic differences in spontaneous recovery in the neurovascular unit between Ovx and Sham females in the chronic stage of stroke, underscoring the importance of considering hormonal-dependent aspects of the ischemic sequelae in the development of novel therapeutic approaches and patient recruitment in clinical trials.
Highlights
Epidemiological evidence suggests lower risk of stroke among premenopausal women than among age-matched men (Stegmayr et al, 1997; Sudlow and Warlow, 1997)
It is known from clinical studies that bilateral oophorectomy in premenopausal women and the consequent drop in ovarian hormonal levels are associated with increased multimorbidity with 18 defined chronic conditions (Levine et al, 2016; Rocca et al, 2017)
New studies [(Biernaskie et al, 2001) and references therein] proposed and supported the notion of a timing hypothesis, which posits that estrogen replacement therapy (ERT) exerts beneficial effects in patients younger than 50 years and starts becoming detrimental for women older than 60, if administered orally
Summary
Epidemiological evidence suggests lower risk of stroke among premenopausal women than among age-matched men (Stegmayr et al, 1997; Sudlow and Warlow, 1997). By the perimenopausal years (55- to 64-year olds), the stroke risk for women equalizes to that of age-matched men (Anderson et al, 1991). Post-ischemic Neurovascular Recovery in Female Rats report (Levine et al, 2016) suggested that bilateral oophorectomy accelerates aging ( of the circulatory system), as measured by increased methylation. Women undergoing oophorectomy (i.e., surgical menopause) show lower levels of estrogen than age-matched women experiencing natural menopause (Korse et al, 2009). While the epidemiological evidence clearly shows that sex and estrogen levels are important factors in the risk of stroke and in its long-term outcome, the mechanism of these dependencies is unclear. Neurovascular functioning in the chronic stage post ischemia in females, and its dependence on ovariectomy and estrogen decline, has not been evaluated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
