Sex-specific acute cerebrovascular response to photothrombotic stroke in mice requires rho-kinase
Bibliographic record
Abstract
Abstract With high energy consumption and low energy storage, the brain is highly reliant on continuous cerebral blood flow (CBF) that delivers substrates to maintain proper function, which is compromised after a stroke. The current study explores the overlapping roles played by two important modulators of cerebrovascular tone, rho-kinase (ROCK) and endogenous sex hormones, in the acute CBF responses to a photothrombotic (PT) model of ischemic stroke in ROCK2 +/- mice and wild-type (WT) littermates. To remove endogenous hormones, male mice were gonadectomized and female mice were ovariectomized, whereas control (“intact”) animals received a sham surgery prior to stroke induction. Intact WT males showed a delayed drop in CBF compared to intact WT females, where maximal CBF drop was observed 48 hours following stroke. Gonadectomy in males did not alter this response, however ovariectomy in females produced a “male-like” response. Intact ROCK2 +/- males also showed such phenotypic response, which was not altered by gonadectomy. Alternatively, intact ROCK2 +/- females showed a striking difference in CBF values compared to intact WT females, where they displayed higher CBF values immediately post-stroke and also showed a maximal CBF drop 48 hours post-stroke, which was not altered by ovariectomy. Overall, there is a marked sex difference in acute CBF responses to PT stroke, which appears to be mediated by endogenous female sex hormones and ROCK2. This study reveals important sex-differences and the involvement of ROCK2 in acute CBF responses to PT stroke in mice. Significance Statement There are very few mechanistic investigations on disparities between sexes in post-stroke CBF outcome. Rho-kinase, an important regulator of vascular tone, has only been explored in males in terms of its modulation of CBF following stroke. Both rho-kinase and endogenous female sex hormones have a converging role on the regulation of endothelial nitric oxide synthase (eNOS), an important modulator of vascular tone. Rho-kinase is thought to elicit its neuroprotective effects against ischemic stroke through eNOS, however this has never been investigated in both sexes. Elucidating the cellular and molecular bases of sex differences in cerebrovascular pathophysiology is vital for understanding the origins of stroke outcomes, and for designing novel therapeutic strategies to promote functional recovery in both women and men.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".