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.

Figure 1. Schematic illustrations of (a) CCM and (b) AVM angioarchitecture

Figure 2. One possible model of genes and pathways involved in CCM signaling

CCM proteins form a molecular complex which interacts closely with cytoskeletal proteins and modulates inter-endothelial cell junctions. Mutations in one copy of a CCM gene may predispose to vascular permeability, which in turn may result in vascular leakage and vulnerability to form dysmorphic vessels. Somatic mutations in the same genetic pathway, immune responses, or altered capillary permeability after radiation injury all might act as “second hits” favoring CCM genesis or maintenance. Abbreviations: β-cat, β-catenin; CCM, cerebral cavernous malformation; ICAP-1, integrin cytoplasmic domain- associated protein-1; ITGβ1, integrin β1; JNK, JUN NH₂-terminal kinase; MEKK3, mitogen-activated protein kinase kinase kinase 3; RAP-1, Ras-proximate-1.

Figure 3. One possible model of genes and pathways involved in AVM pathogenesis

The genes associated AVM formation (shown in red) lie in the TGFβ superfamily signaling pathway. TGFβ and BMPs bind to TGFβRII and BMPRII, respectively. Upon ligand binding, the type II receptors phosphorylate associated type I receptors (ALK1, 3, 4, 5, or 6). The ALKs in turn recruit and phosphorylate receptor-regulated Smads (Smads 1, 5, and 8 or Smads 2 and 3). The receptor-regulated Smads form complexes with the common mediator, Smad 4, and translocate to the nucleus to participate in regulating the transcription of target genes. Endoglin is a TGF-β co-receptor that can modulates signaling through either the TGF-β or BMP membrane-bound signaling complexes. Endoglin also exists in a soluble, extracellular form (sEndoglin) that can bind and sequester BMPs or TGF-βs. Mutations of the genes shown in red may lead to dysregulation of processes required for blood vessel wall stabilization. In susceptible patients, formation of an AVM may then result from a defective repair response to an otherwise minor insult. Abbreviations: ALK, activin-like kinase receptor; BMP, bone morphogenetic protein; BMP-RII, BMP receptor type II; sEndoglin, soluble Endoglin; TGF β, transforming growth factor β; TGF β -RII, TGF β receptor type II.