Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation

Astrocytes are intimately linked with brain vessels, a relationship that is critical for neuronal health and function. However, key astroglial molecular factors that drive these physical and functional associations during postnatal brain development have not yet been 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 to then decreased rapidly. Astrocyte-selective ablation of Hmgb1 in newborn mice affected astrocyte morphology and endfoot placement, induced disruption of endfoot proteins connexin43 and aquaporin-4, induced transcriptional changes in astrocytes, and profoundly altered endothelial cell ultrastructure. While lack of astroglial Hmgb1 did not affect the blood-brain barrier or angiogenesis postnatally, it impaired neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as a key player in postnatal gliovascular maturation. 16  RNA samples were used for RNA sequencing (4 mutant endothelial cell samples and 4 mutant astrocytes cell samples were isolated from 4 mutant animals; 4 wild type endothelial cell samples and 4 wild type astrocytes cell samples were isolated from 4 wild type animals).