Biology of Vascular Malformations of the Brain

Abstract

Background and Purpose-This review discusses recent research on the genetic, molecular, cellular, and developmental mechanisms underlying the etiology of vascular malformations of the brain (VMBs), including cerebral cavernous malformation, sporadic brain arteriovenous malformation, and the arteriovenous malformations of hereditary hemorrhagic telangiectasia. Summary of Review-The identification of gene mutations and genetic risk factors associated with cerebral cavernous malformation, hereditary hemorrhagic telangiectasia, and sporadic arteriovenous malformation has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases, cerebral cavernous malformation lesion formation involves a genetic 2-hit mechanism in which a germline mutation in one copy of a cerebral cavernous malformation gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene. Conclusions-Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further progress will be facilitated by collaborative expansion and standardization of these. (Stroke. 2009;40:e694-e702.)

Are parenchymal AVMs congenital lesions?

“…19,20,22 Studies of AVM tissue have shown increased endothelial cell proliferation and increased expression of angiopoietin-2 and vascular endothelial growth factor, which promote vascular destabilization and proliferation, respectively. 17 However, the exact triggering event that leads to increased and disorganized angiogenesis ultimately leading to AVM formation has not been identified.…”

“…8 This finding suggests that the presence of a genetic abnormality alone is not enough to trigger AVM formation and a "second hit" is required. 22 A possible mechanism to explain AVM formation may not be dissimilar to that responsible for dural arteriovenous fistulas-that is, venous thrombosis leading to impaired venous outflow, ischemia, and increased angiogenesis. 1 In the case of brain AVMs, asymptomatic parenchymal venous thrombosis could trigger local venous hypertension and ischemia.…”

“…12 However, in the presence of genetic susceptibility and abnormalities of the angiogenesis and inflammatory cascades, there may be uncontrolled vascular proliferation and arteriovenous shunt forma- tion. 22 Once high flow is established through the vascular lesion, endothelial shear stress contributes to a continued angiogenic stimulus and a hyperangiogenic environment. 36 …”

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

“…[44][45][46][47] Homozygous loss of these genes leads to death in utero. 48 ENG and ALK1 are expressed on ECs and bind TGF-β, modulating EC proliferation, migration, adhesion, and apoptosis. 49 They are downregulated during adulthood, but are reactivated when the need for vascular repair arises.…”

“…Owing to the extensive involvement of ENG and ALK1 in maintaining vascular stability, missing an allele and thus expressing lower amounts of these proteins leads to vascular dysmorphogenesis and potentially hemorrhage. 48 As part of the TGF-β receptor complex, ENG is also involved in the neovascularization of damaged tissue during inflammation. It binds activated circulating leukocytes, enabling them to adhere to damaged endothelium or ischemic tissues.…”