The blood–brain barrier (BBB) is a biological and functional barrier between the peripheral vascular system and the central nervous system (CNS), which comprises various types of brain cells, including endothelial cells, pericytes, and astrocytes. The BBB strictly limits the influx of intravascular contents, including serum proteins and blood cells, into the CNS to maintain an appropriate environment. In a damaged brain, such as in traumatic brain injury (TBI) and cerebral ischemia, BBB function is remarkably disrupted, and BBB disruption causes brain edema and neuroinflammation resulting from the extravasation of serum proteins and infiltration of inflammatory cells into the cerebral parenchyma (Jha et al., 2019, Michinaga and Koyama, 2017, Sulhan et al., 2020). As these conditions result in unexpected death, coma, ataxia, and cognitive dysfunction, protection and recovery of BBB function are essential therapeutic strategies for acute brain injuries (Alluri et al., 2015, Thal and Neuhaus, 2014, Michinaga and Koyama, 2017).

Astrocytes are the most abundant glial cells in the CNS and support the integrity and function of the BBB via their end-feet surrounding brain microvessels. Under physiological and pathophysiological conditions, various astrocyte-derived bioactive factors alter the permeability of the BBB (Michinaga & Koyama, 2019). In the damaged brain, astrocytes produce the pro-inflammatory cytokines endothelin-1 (ET-1), matrix metalloproteinase 9 (MMP9), and vascular endothelial growth factor-A (VEGF-A), which significantly promote BBB permeability and deteriorate BBB disruption (Didier et al., 2003; Argaw et al., 2012; Lo et al., 2005; Michinaga et al., 2018; Min et al., 2015). However, some astrocyte-derived bioactive factors decrease BBB permeability and reduce BBB disruption in the damaged brain (Michinaga & Koyama, 2019). Sonic hedgehogs (Shh) are astrocytic factors. Previous studies have shown that altered expression of astrocytic Shh in the damaged brain is involved in the reduction of BBB function and that activation of Shh signaling has a protective effect on the BBB. In this review, recent findings on the roles of astrocytic Shh and Shh signaling in BBB function are summarized, and the significance of the development of novel therapeutic drugs targeting Shh or Shh signaling is discussed.