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Gene & Protein in Disease Genetics of arteriovenous malformations

due to deficient pericyte recruitment and vascularization Elucidating these epigenetic signals has been approached
(Figure 2) [9,16] . Pericytes are multifunctional mural cells by several authors. DNA methylation in vascular
that play a role in the regulation of brain angiogenesis, development has been shown to impact the atherogenesis
blood-brain barrier (BBB) integrity, and vascular process at the endothelial cell level . Chan et al. reported
[42]
stability . Reduced pericyte migration in bAVM can that promoter DNA methylation plays an important
[38]
also result in increased rate of blood flow through the role in the cell-specific expression of the constitutively
lesion and therefore increased risk for microhemorrhages expressed endothelial nitric-oxide synthase (eNOS) gene
in unruptured bAVM . In addition, Shaligram et al. in the vascular endothelium . Rao et al. proposed that
[38]
[43]
reported that the dysregulation of angiopoietin-1 and methyl-CpG-binding domain protein 2 (MBD2), an
angiopoietin-2 results in increased BBB permeability and interpreter for DNA methylome-encoded information,
risk for bAVM rupture . In addition, it has been reported could be a worthwhile epigenetic target for modifying
[9]
that 30% of bAVM overexpress angiopoietin-2, signifying endothelial function because of its associated role in
the need to further explore its role in bAVM . VEGF signaling .
[44]
[39]
The role of non-coding RNAs in AVM pathogenesis Variations in histone modifications have also been
has also gained increased attention in the literature. implicated in AVM pathogenesis. Histone acetylation
Chen et al. identified three critical microRNAs has been shown to be impacted by hemodynamic forces
(miRNAs) involved in VEGF signaling in blood and blood flow through enzymatic changes of histone
samples of patients with bAVM compared to healthy acetyl transferases (HATs) . Lee et al. showed that
[45]
controls: miR-7-5p, miR-199a-5p, and miR-200b-3p [40] . HDAC molecules play a regulatory role in oxidative,
Therapeutic approaches to targeting VEGF via the use inflammatory, and proliferative responses of endothelial
of small interfering RNAs have also been reported [41] . cells in response to disturbed flow with oscillatory shear
Identification of these miRNA can provide insight on the stress . These changes in blood flow result in post-
[46]
role of these noncoding aspects in bAVM pathogenesis translational modifications in chromatin structure . The
[46]
and future studies are warranted. role of histone deacetylase 7 (HDAC7) functioning has also
been implicated in angiogenesis, and its downregulation
3.3. Epigenetic mechanisms in AVM formation results in impaired vascular growth .
[47]
Understanding the epigenetic landscape is also important The current breadth of literature elucidating the genetic
to decipher the formation and growth of AVM lesion. mechanisms at play and their impact on the signaling
Transcriptional and metabolite level changes have been pathways in bAVM formation provides an opportunity
shown to play a role in the angiogenesis of AVM . for the future therapeutic options. Next, we provide a
[34]
summary of the most supported candidate genes associated
with AVM.

4. Candidate genes involved in AVM
formation
Several candidate genes have been implicated in the
development of AVM for their involvement in the
regulation of blood vessel formation, signaling pathways,
and cell proliferation.
Mitogen activated protein kinase kinase 1 (MAP2K1)
is the gene that codes for MAP-extracellular signal-
regulated kinase 1 (MEK1). This gene produces a protein
that belongs to the family of dual specificity protein
kinases and functions as a mitogen-activated protein
Figure 2. The role of PDGFB in bAVM pathogenesis. Schematic of kinase. MAP kinases serve as an integration point for
hypothesized relationship between decreased expression of PDGFB many biochemical signals. This kinase, located upstream
and bAVM. Pericytes are thought to be key mediators in this pathway. of MAP kinases, activates their enzymatic activity in
Decreased expression of PDGFB results in aberrant PDGFB signaling and response to various intracellular and extracellular signals.
resultant deficient pericyte recruitment and vascularization and eventual It is involved in numerous cellular activities, including
bAVM formation.
Abbreviations: PDGFB: Platelet-derived growth factor subunit B; proliferation, differentiation, determination, transcription
bAVM: Arteriovenous malformations of the brain. control, apoptosis, and development [48,49] . It is a crucial

Volume 2 Issue 2 (2023) 5 https://doi.org/10.36922/gpd.0312