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Astrocytes are intimately linked with brain vessels, a relationship that is critical for neuronal health and function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. We characterized structural and transcriptional changes in mouse cortical astrocytes and microvessels during the first two postnatal weeks and found that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, was highly expressed in astrocytes at birth and then decreased rapidly. Astrocyte-selective ablation ofHmgb1at birth affected astrocyte morphology and endfoot placement, altered distribution of endfoot proteins connexin43 and aquaporin-4, induced transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupted endothelial ultrastructure. While lack of astroglialHmgb1did not affect the blood-brain barrier or angiogenesis postnatally, it impaired neurovascular coupling and behavior in adult mice. These findings identify astroglialHmgb1as a key player in postnatal gliovascular maturation.

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 StatementThere 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.

The blood-brain barrier (BBB) protects the central nervous system (CNS) from harmful blood-borne factors. Although BBB dysfunction is a hallmark of several neurological disorders, therapies to restore BBB function are lacking. An attractive strategy is to repurpose developmental BBB regulators, such as Wnt7a, into BBB-protective agents. However, safe therapeutic use of Wnt ligands is complicated by their pleiotropic Frizzled signaling activities. Taking advantage of the Wnt7a/b-specific Gpr124/Reck co-receptor complex, we genetically engineered Wnt7a ligands into BBB-specific Wnt activators. In a “hit-and-run” adeno-associated virus–assisted CNS gene delivery setting, these new Gpr124/Reck-specific agonists protected BBB function, thereby mitigating glioblastoma expansion and ischemic stroke infarction. This work reveals that the signaling specificity of Wnt ligands is adjustable and defines a modality to treat CNS disorders by normalizing the BBB.