LAUSR

The morphogen Sonic hedgehog (Shh) is crucial for the embryonic development of the central nervous system, but is also an important player in the postnatal brain, with activities that range from the modulation of self-renewal and specification of neural stem cells to the regulation of neural regeneration after injury. Active Shh signaling occurs also in molecular subclasses of brain tumors, such as medulloblastoma and adult glioma. In some cases, Shh-responsive cells may even be the brain tumor cells of origin. We have recently identified a novel possible role for Shh in the post-natal brain, which is a contribution to the pathogenesis of arteviovenous malformations (AVMs). Bra in AVMs are abnormal tangles of vessels which directly shunt blood from the arterial to the venous circulation without an interposed capillary bed. They are an important cause of intracranial hemorrhage and account for about 50% of strokes in childhood. Despite intense investigation, etiology and pathogenesis of brain AVMs remain poorly understood and this hinders the development of effective therapeutic strategies. In this article, we summarize the results of our recent study, in which we demonstrated that the Shh signaling pathway is aberrantly active in the endothelium of human brain AVMs and that stereotactic injection of Shh in the rat brain results in an angiogenic response that displays many of the features that are typical of AVMs, such as the presence of dilated, tortuous, and entangled arterial and venous vessels interconnected to each other by direct arteriovenous shunts. In this article, we also discuss the multiple mechanisms potentially responsible for the upregulation of the Shh pathway in AVMs and those through which Shh might contribute to the pathogenesis of AVMs, including abnormal angiogenesis, alterations of the blood-brain barrier, and promotion of survival and inhibition of apoptosis of neural and endothelial cells. Finally, we discuss the clinical and therapeutic implications of a potential involvement of the Shh pathway in brain AVM pathobiology, including the possibility to use anti-Shh molecules for the treatment of brain AVMs in humans.