Brain arteriovenous malformation in hereditary hemorrhagic telangiectasia: Recent advances in cellular and molecular mechanisms

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by vessel dilatation, such as telangiectasia in skin and mucosa and arteriovenous malformations (AVM) in internal organs such as the gastrointestinal tract, lungs, and brain. AVMs are fragile and tortuous vascular anomalies that directly connect arteries and veins, bypassing healthy capillaries. Mutations in transforming growth factor β (TGFβ) signaling pathway components, such as ENG (ENDOGLIN), ACVRL1 (ALK1), and SMAD4 (SMAD4) genes, account for most of HHT cases. 10-20% of HHT patients develop brain AVMs (bAVMs), which can lead to vessel wall rupture and intracranial hemorrhages. Though the main mutations are known, mechanisms leading to AVM formation are unclear, partially due to lack of animal models. Recent mouse models allowed significant advances in our understanding of AVMs. Endothelial-specific deletion of either Acvrl1, Eng or Smad4 is sufficient to induce AVMs, identifying endothelial cells (ECs) as primary targets of BMP signaling to promote vascular integrity. Loss of ALK1/ENG/SMAD4 signaling is associated with NOTCH signaling defects and abnormal arteriovenous EC differentiation. Moreover, cumulative evidence suggests that AVMs originate from venous ECs with defective flow-migration coupling and excessive proliferation. Mutant ECs show an increase of PI3K/AKT signaling and inhibitors of this signaling pathway rescue AVMs in HHT mouse models, revealing new therapeutic avenues. In this review, we will summarize recent advances and current knowledge of mechanisms controlling the pathogenesis of bAVMs, and discuss unresolved questions.

Keywords: ALK1; AVM; BMP; ENG; HHT; SMAD4; endothelial cells.

FIGURE 1

Endothelial BMP/ALK1 signaling pathway. Soluble BMP9 and BMP10, secreted, respectively, by the liver and the heart in the bloodstream, bind their receptor ALK1, a SER/THR kinase, and its coreceptors BMPRII and ENDOGLIN at the surface of ECs. The activation of the BMP receptor complex will trigger the downstream SMAD signaling. Phosphorylated SMAD1/5/8 will recruit SMAD4. This SMAD complex accumulates in nucleus to regulate transcription of target genes, including genes involved in angiogenic processes.

FIGURE 2

Signaling pathways known to be involved in the pathogenesis of AVMs. In healthy capillary networks, blood flow potentiates BMP/ALK1 signaling pathway in ECs to regulate the expression of genes involved in arterio-venous specification and NOTCH signaling pathway. BMP/ALK1/SMAD4 pathway will inhibit blood flow- and VEGFR2-induced PI3K/AKT signaling. Indeed SMAD4 inhibits the expression of CK2, which allows the phosphorylation, and inhibition of PTEN, a negative regulator of the PI3K/AKT signaling, which will promote ECs quiescence and polarization against the flow. HHT1, HHT2, JP-HHT, and HHT5 are induced by ENG, ACVRL1 (ALK1), SMAD4, and GDF2 (BMP9) heterozygous mutations, respectively. CK2 inhibition is removed and its expression increases leading to an enhanced phosphorylation of PTEN which will not be able to inhibit PI3K/AKT signaling induced by blood flow and VEGFR2. Increased AKT phosphorylation leads to higher YAP/TAZ expression and activity, hyperproliferation of ECs and migration defects against the flow.