• Major finding: Disruption of SMO-dependent signaling increases blood–brain barrier permeability.

  • Mechanism: Perivascular astrocytes secrete SHH, and endothelial cells express PTCH-1 and SMO.

  • Impact: Modulation of Hedgehog signaling could affect drug delivery or cell migration to the CNS.

The blood–brain barrier (BBB) limits the entry of blood-borne molecules to the central nervous system (CNS) and thus poses a significant obstacle to the delivery of systemic chemotherapy. The BBB consists of specialized endothelial cells that are tightly bound by junctional proteins to restrict the passage of solutes and astrocytes that surround the CNS vasculature. Alvarez and colleagues investigated the role of the Hedgehog (Hh) pathway in the maintenance of BBB integrity because deregulated Hh signaling and BBB disruption are common features of multiple sclerosis, which is marked by aberrant entry of circulating leukocytes into the CNS and subsequent demyelination and neuronal damage. Sonic hedgehog (SHH) expression was observed in cultured human astrocytes, and active, secreted SHH was present in astrocyte-conditioned media. BBB endothelial cells did not express SHH but expressed high levels of the SHH receptor components Patched-1 (PTCH-1) and Smoothened (SMO), suggesting that astrocyte-mediated paracrine signaling activates the Hh pathway in BBB endothelial cells. Systemic pharmacologic disruption of Hh signaling with cyclopamine or conditional deletion of Smo in endothelial cells increased BBB permeability in mice as measured by serum protein and leukocyte CNS extravasation, which was correlated with decreased junctional protein expression. These findings provide insight into the maintenance of BBB integrity and suggest that pharmacologic modulation of BBB permeability has the potential to improve delivery of chemotherapeutic agents to the brain or prevent migration of cancer cells into the CNS.

Alvarez JI, Dodelet-Devillers A, Kebir H, Ifergan I, Fabre PJ, Terouz S, et al. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 2011;334:1727–31.

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