Genetics and Vascular Biology of Brain Vascular Malformations

Cerebrovascular malformations are a major cause of intracranial hemorrhage in young adults and children. They are resource-intensive to manage with invasive treatment modalities, and there is no current medical therapy option available for patients. A better understanding of the genetics and biology of cerebrovascular malformations is needed to elucidate common biologic mechanisms and potential therapeutic targets. Different cerebrovascular malformations have varying genetic etiology but share commonalities in signaling pathways affecting angiogenesis, vascular remodeling, inflammation, and response to injury. Inherited mutations underlie hereditary hemorrhagic telangiectasia (HHT), cerebral cavernous malformations (CCMs), capillary malformation-arteriovenous malformation (CM-AVM), and venous malformations. Somatic mutations have now been identified in most cerebrovascular malformations, including most recently for sporadic brain AVM, further suggesting common pathways affecting downstream ERK signaling as a potential therapeutic target. Additional modifier genes and other factors are emerging as important predictors explaining the variable expressivity of the disease and may shed light on the progression of these related vascular malformations. In this chapter, we focus on the vascular biology and genetics of brain AVMs and CCMs; other cerebrovascular malformations are also discussed briefly.