Oophorectomy Reduces Estradiol Levels and Long-Term Spontaneous Neurovascular Recovery in a Female Rat Model of Focal Ischemic Stroke

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.

Combinatorial Treatment Using Umbilical Cord Perivascular Cells and Aβ Clearance Rescues Vascular Function Following Transient Hypertension in a Rat Model of Alzheimer Disease

“…In parallel, responsivity to hypercapnia increased from 38.7±10.5% at baseline to 82.3±14.4% post– l -NAME ( P =0.026) and then recovered to 64.9±21.6% at end point ( P =0.28 when compared with baseline, Figure 2A). Reduced resting perfusion yet elevated cerebrovascular responsivity to hypercapnia is a pattern also observed in the subacute stage after cortical ischemia, 34,35,39 where it has been shown to underlie metabolic dysfunction and to correlate to the extent of inflammation and neurovascular damage. At end point, nontransgenic animals showed resting perfusion and responsivity to hypercapnia similar to nontransgenic animals at baseline (resting perfusion: 93.1±17 versus 76.7±0.96 mL/[min·100 mL] tissue, P =0.12; hypercapnia challenges: 57.7±23.1 versus 37.8±11.1%, P =0.65).…”

“…Continuous arterial spin labeling magnetic resonance imaging was performed at baseline, post– l -NAME, and end point to measure cerebrovascular reactivity changes over time; continuous arterial spin labeling data were analyzed as described previously. 34,35 Subject-specific hemodynamic response functions were produced by averaging the signal over the thalamic nuclei: this region was used to define reference hemodynamic response function as it spared from amyloid pathology at this stage of the disease (Figure S1).…”

Frequency selective neuronal modulation triggers spreading depolarizations in the rat endothelin-1 model of stroke

“…Careful placement of the pipettes is of critical importance to avoid major damage to parenchyma and CSD triggering, as described in our previous studies. 51 – 54 Before ET-1 injection, we illuminated the cortex with 450 nm light at different frequency bands (theta, alpha, beta, low gamma, and high gamma) for 60 s, with 60-s interstimulus interval, and with stimulus frequency bands presented in random order. Figure 4 (Bi) and (Bii) show representative optogenetic stimulation at different bands at “baseline” and during “partial vRBC recovery,” respectively.…”

Micro-ultrasound based characterization of cerebrovasculature following focal ischemic stroke and upon short-term rehabilitation

“… 74 Using mature peri-menopausal female rats, we previously demonstrated a significant decrease in peri-lesional cerebral blood flow with CASL-MRI, reduced peri-lesional neuronal activity, and reduced neuronal power of theta:low gamma electrophysiological recordings in ovariectomized versus intact females. 77 The clear link between neurovascular function with circulating estrogen regulating ischemic damage and recovery, supports the need for novel sex-based therapies in the chronic post-stroke recovery period. This necessitates well designed, age-matched, and physiologically relevant male versus female studies throughout all stages of life.…”