Sex Difference in Capillary Reperfusion After Transient Middle Cerebral Artery Occlusion in Diabetic Mice

Abstract

Background: Type 2 diabetes (DM2) exacerbates stroke injury, reduces efficacy of endovascular therapy, and worsens long-term functional outcome. Sex differences exist in stroke incidence, response to therapy, poststroke microvascular dysfunction, and functional recovery. In this study, we tested the hypotheses that poor outcome after stroke in the setting of DM2 is linked to impaired microvascular tissue reperfusion and that male and female DM2 mice exhibit different microvascular reperfusion response after transient middle cerebral artery occlusion (MCAO). Methods: Transient MCAO was induced for 60 minutes using an intraluminal filament in young adult DM2 and nondiabetic control male and female mice. Capillary flux in deep cortical layers was assessed using optical coherence tomography–based optical microangiography (OMAG), and associated regional brain infarct size was evaluated by hematoxylin and eosin staining. Results: Compared to baseline, MCAO reduced absolute capillary red blood cell flux by 84% at 24 hours post-MCAO in male DM2 ( P <0.001) but not male control mice. When normalized to pre-MCAO baseline, red blood cell flux 24 hours after stroke was 64% lower in male DM2 mice than male nondiabetic controls ( P <0.01). In females, MCAO decreased capillary flux by 48% at 24 hours post-MCAO compared with baseline in DM2 ( P <0.05) but not in control mice. Red blood cell flux of female DM2 mice did not differ from that of nondiabetic controls either before or 24 hours after MCAO. Furthermore, normalized capillary flux 24 hours after MCAO failed to differ between female DM2 mice and nondiabetic controls. Concomitantly, male but not female DM2 mice experienced 25% larger infarct in caudate-putamen versus respective nondiabetic controls ( P <0.05). Conclusions: DM2 impairs capillary perfusion and exacerbates ischemic deep brain injury in male but not female young adult mice. Premenopausal females appear to be protected against DM2-related capillary dysfunction and brain injury.

Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury

“…7a ). Because previous studies suggested that premenopausal females were protected against capillary dysfunction and brain injury under particular conditions 35 , we subjected only male mice to MCAO to evaluate the effects of GPR30 in ischaemia-reperfusion injury. Milder ischaemia-reperfusion injury was seen in two lines of GPR30-deficient mice ( Gpr30 Venus / Venus and Gpr30 −/− ) than in Gpr30 +/ Venus and Gpr30 +/+ mice, respectively (Fig.…”

“…We subjected only male mice to MCAO to evaluate the effects of GPR30 in ischaemia-reperfusion injury because previous studies suggested that premenopausal females are protected against capillary dysfunction and brain injury in particular conditions 35 . Mice were anaesthetised with 5.0% isoflurane (Abbott Japan Co., Ltd., Tokyo, Japan) and maintained with 2.0% isoflurane in 70% N 2 O and 30% O 2 using a small-animal anaesthesia system.…”

Inhibition of leukocyte migration after ischemic stroke by VE‐cadherin mutation in a mouse model leads to reduced infarct volumes and improved motor skills

“…Focal transient ischemic stroke was induced through 45 min of transient MCAO, as previously described (Gelderblom et al., 2009 ; Gliem et al., 2012 ; Schmidt‐Pogoda et al., 2018 ; Zhu et al., 2023 ). In brief, the procedure was performed under inhalation anesthesia with 1.5% isoflurane in 30% O 2 /70% N 2 O and maintenance of a constant body temperature of 37 ± 0.5°C.…”

NRF2 activation ameliorates blood–brain barrier injury after cerebral ischemic stroke by regulating ferroptosis and inflammation

“…The thread was terminated in the case of resistance. After suture removal 1 h later, the mice recovered for 6 h, 24 h, 3 d, 5 d, and 7 d 28 . Sham mice received an identical procedure without inserting the intraluminal filament.…”