Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Molecular Biology and Novel Treatments of Intracranial AVMs


Acknowledgments

We thank the staff of Neuroscience Publications at Barrow Neurological Institute for assistance with manuscript preparation.

Pearls

  • The dynamic nature of iAVMs is ascribed to complex molecular and physiologic processes that contribute to their growth, regression, remodeling, and de novo recurrence.

  • Endothelial cell–specific, somatic-activating mutations in the KRAS gene contribute to the formation of sporadic iAVMs.

  • Hereditary hemorrhagic telangiectasia is the most prevalent genetic syndrome associated with the formation of AVMs and has been linked to loss-of-function mutations in ENG , ALK1 , and SMAD4.

  • The overexpression of vascular endothelial growth factor (VEGF) significantly contributes to disruption in angiogenesis in genetic and sporadic iAVMs.

  • The identification and characterization of signaling pathways, including VEGF, mitogen-activated protein kinase–extracellular signal-regulated kinase (MAPK-ERK), transforming growth factor (TGF)-β, and inflammatory cytokines, hold promise for anti-AVM drug therapies.

Cellular and Molecular Biology of AVMs

Intracranial arteriovenous malformations (iAVMs) are dysplastic tangles of feeding arteries and draining veins that lack an interposing capillary bed. The direct shunting of blood creates a high-pressure, low-resistance nidus with a high risk of spontaneous rupture and life-threatening intracerebral hemorrhage. AVMs are dynamic vascular networks with underlying complex physiologic and molecular processes that enable these lesions to grow, regress, remodel, and even reappear after successful resection. Vascular remodeling occurs secondary to high arterial pressure, flow turbulence, compartmentalization, and vascular steal. Increased mechanical stress on the vessel walls then leads to the activation of molecular signaling pathways in smooth muscle cells and brain endothelial cells. The hallmarks of AVM morphology are heterogeneity in vessel size and wall thickness, splitting of the elastic lamina, thickening of the endothelial layer, endothelial cushions, lack of tight junctions, and increased collagen and lymphocytic infiltration.

AVM pathogenesis has been linked to genetic mutations in inflammation, angiogenesis, vasculogenesis, and cell structure integrity. Genome-wide RNA sequencing of human AVM specimens identified 736 upregulated and 498 downregulated genes in iAVMs. Upregulated genes are implicated in the cytoskeletal system, cell migration, and secretion of inflammatory cytokines and secretory products of neutrophils and macrophages. Downregulated genes encompassed functions in extracellular matrix composition, the angiopoietin-TIE system, and transforming growth factor (TGF)-β signaling. iAVMs feature a unique genetic signature indicating that inflammatory processes, loss of endothelial quiescence, and impaired brain-blood barrier integrity contribute to growth and remodeling.

SINGLE-NUCLEOTIDE polymorphisms

Single-nucleotide polymorphisms, genomic single-base variations among members of a biological species, have been correlated with sporadic iAVM susceptibility and risk of hemorrhage. Genomic polymorphisms in angiogenic ALK1 (activin A receptor–like type 1 gene) and ANGPTL4 (angiopoietin-like protein 4 gene) are significantly associated with disease susceptibility, and single-nucleotide polymorphisms in the inflammatory genes IL6 and TNFα are significantly associated with increased risk of rupture. Other genes associated with sporadic AVM development are IL1A/B , TGFRB2 , MMP-3 , ALK1 , and VEGFA . Along with loci in IL6 , TNFA , IL1B , IL17A , and APOE , angiogenic gene polymorphisms in EPHB4 and VEGFA are linked with increased bleeding risk in spontaneous AVMs.

Vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) functions as a crucial signal mediator of angiogenesis in sporadic and hereditary iAVMs. VEGF-deficient mice fail to develop proper cardinal vasculature during embryogenesis. Although VEGF signaling is quiescent in normal adult vasculature, it is overexpressed in recurrent AVMs in children. However, when cerebral hypoxia is sensed through oxygen-dependent molecules, including hypoxia-inducible factor 1-, VEGF is rapidly secreted by astrocytes. Neutralization of VEGF overexpression using the monoclonal antibody bevacizumab blocked cutaneous AVM formation in Alk1 -knockout mice and normalized arteriovenous shunting.

Somatic-activating mutations in KRAS

Whole-genome sequencing identified somatic-activating mutations in the KRAS (Kirsten rat sarcoma viral oncogene homolog) gene in sporadic human iAVMs. KRAS is a signal mediator protein that activates various downstream pathways, including rat fibrosarcoma–mitogen-activated protein kinase kinase–extracellular signal–regulated kinase (RAF-MEK-ERK), and phosphatidylinositol-3 kinase-protein kinase B–mammalian target of rapamycin (PI3K-Akt-mTOR) signaling. Depending on which pathway is dysregulated, differentiation into a phenotypic slow-flow (PI3K pathway) AVM or a high-flow (rat sarcoma–mitogen-activated protein kinase [RAS-MAPK]) AVM ensues. The localized detection of KRAS mutations in endothelial cells but not in endothelial cell–deficient tissue suggests impaired endothelial function in AVM pathogenesis.

Inflammatory cytokines

Inflammation is an essential component of AVM pathogenesis and is mediated through cytokines and zinc-containing matrix metalloproteinases (MMPs). Interleukin (IL)-6 is a proinflammatory acute-phase reactant that promotes vascular instability by the release of MMPs. High-expression levels of IL-6 and MMPs have been correlated with rupture of iAVMs. Along with the coexpression of IL-1β, tumor necrosis factor (TNF)-α, IL-8, MMP-3, MMP-9, and MMP-12, IL-6 enhances VEGF signaling and promotes AVM progression and remodeling.

Pericytes

In a healthy brain, blood vessel integrity is maintained by abundant pericyte coverage. Pericytes adhere to the endothelial cells of capillaries and venules. Blood vessels of iAVMs are prone to rupture due to insufficient pericyte recruitment, resulting in blood vessel instability. Platelet-derived growth factor subunit B (PDGFB) and its corresponding receptor PDGF receptor beta (PDGFRB) are crucial for adequate pericyte and vascular smooth muscle recruitment during angiogenesis. Endothelial cells of Pdgfb -deficient mice were unable to recruit pericytes, resulting in blood vessel rupture. Reduction in pericyte coverage in human iAVMs has been found to correlate with faster blood flow through the nidus. These hemodynamic changes paired with reduced numbers and poor pericyte function were associated with more severe microhemorrhages in unruptured human iAVMs.

Angiopoietins

Angiopoietins belong to the family of vascular growth factors and mediate angiogenesis during embryogenesis and in the postnatal period by regulating proper pericyte and smooth muscle cell migration. Angiopoietin-2 has been associated with both angiogenesis and inflammation, and its blockage leads to complete reversal of iAVMs in vivo. Angiopoietin-2 overexpression in human iAVMs is estimated at 30%, and angiopoietin-2 presents a suitable target for anti-AVM drugs.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts