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Modulation of the Acute Cerebrovascular Response to Ischemic Stroke by Sex Hormones is Dependent on Rho‐kinase

Ischemic stroke, resulting from the occlusion of a cerebral blood vessel, leads to reduced cerebral blood flow (CBF) and neuronal death. Very little is known about the cellular and molecular underpinnings of sex differences in vascular outcomes of cerebral ischemia. CBF in the healthy brain is primarily regulated by vasomodulators secreted from endothelial cells, particularly through the action of endothelial nitric oxide synthase (eNOS). Rho‐associated protein kinase (ROCK) is another major regulator of endothelial function and cell contractility, and has inhibitory effects on eNOS. Pharmacological blockade of ROCK, and heterozygous deletion of ROCK2, the isoform found predominantly in the brain and endothelium, both have neuroprotective effects against ischemic stroke. The regulation of CBF following ischemic stroke has not been well characterized in animal models. The aim of the current study was to determine the contribution of ROCK in the regulation of CBF following ischemic stroke between sexes in ROCK2+/‐ mice. In sham or gonadectomized male and female mice, CBF was measured using laser doppler flowmetry before and after photothrombotic (PT) stroke. Intact Wild‐Type (WT) females showed an immediate ~50% reduction in CBF compared to baseline following PT, whereas intact WT males surprisingly showed no immediate reduction, with male CBF dropping only 48 hours post‐PT. At 48 hours post‐stroke, CBF values became comparable between intact WT males and females. Gonadectomy of WT female mice resulted in similar CBF patterns as in intact WT males. Male and female ROCK2+/‐ mice displayed similar CBF responses as intact WT females. Gonadectomy of males did not change the acute CBF response to PT stroke. Interestingly, ROCK2+/‐ mice have been shown to have constitutively‐increased eNOS expression in brain endothelial cells. eNOS, an important mediator in the regulation of CBF, is also largely regulated by estrogens, and therefore may be partly responsible for these results. This study provides novel insight into the role of sex hormones in cerebrovascular responses to stroke. It is vital to understand the nature and origins of sex‐specific stroke outcomes in order to design novel therapies with optimal effectiveness in women and men.