An Insight into the microRNAs Associated with Arteriovenous and Cavernous Malformations of the Brain

Abstract

Background: Brain arteriovenous malformations (BAVMs) and cerebral cavernous malformations (CCMs) are rare developmental anomalies of the intracranial vasculature, with an irregular tendency to rupture, and as of yet incompletely deciphered pathophysiology. Because of their variety in location, morphology, and size, as well as unpredictable natural history, they represent a management challenge. MicroRNAs (miRNAs) are strands of non-coding RNA of around 20 nucleotides that are able to modulate the expression of target genes by binding completely or partially to their respective complementary sequences. Recent breakthroughs have been made on elucidating their contribution to BAVM and CCM occurrence, growth, and evolution; however, there are still countless gaps in our understanding of the mechanisms involved. Methods: We have searched the Medline (PubMed; PubMed Central) database for pertinent articles on miRNAs and their putative implications in BAVMs and CCMs. To this purpose, we employed various permutations of the terms and idioms: 'arteriovenous malformation', 'AVM', and 'BAVM', or 'cavernous malformation', 'cavernoma', and 'cavernous angioma' on the one hand; and 'microRNA', 'miRNA', and 'miR' on the other. Using cross-reference search; we then investigated additional articles concerning the individual miRNAs identified in other cerebral diseases. Results: Seven miRNAs were discovered to play a role in BAVMs, three of which were downregulated (miR-18a, miR-137, and miR-195*) and four upregulated (miR-7-5p, miR-199a-5p, miR-200b-3p, and let-7b-3p). Similarly, eight miRNAs were identified in CCM in humans and experimental animal models, two being upregulated (miR-27a and mmu-miR-3472a), and six downregulated (miR-125a, miR-361-5p, miR-370-3p, miR-181a-2-3p, miR-95-3p, and let-7b-3p). Conclusions: The following literature review endeavored to address the recent discoveries related to the various implications of miRNAs in the formation and growth of BAVMs and CCMs. Additionally, by presenting other cerebral pathologies correlated with these miRNAs, it aimed to emphasize the potential directions of upcoming research and biological therapies.

Keywords: brain arteriovenous malformations; cerebral cavernous malformations; microRNA.

Figure 1

VEGF signaling pathway in vasculogenesis and angiogenesis. Abbreviations (in alphabetical order): AKT, Protein kinase B; EC, endothelial cell; ECM, endothelial cell membrane; eNOS, nitric oxide synthase; ERK, extracellular signal-regulated kinases; FGF, fibroblast growth factor; MMPs, metalloproteinases; MAPK, mitogen-activated protein kinase; miR, microRNA; PDGF, platelet-derived growth factor; PI3K, Phosphoinositide 3-kinases; PIK3R2, phosphoinositide-3-Kinase Regulatory Subunit 2; PTEN, Phosphatase and tensin homolog; SPRED1, Sprouty Related EVH1 Domain Containing 1; TIMP1/3, tissue inhibitor of metalloproteinases 1/3; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 2

Schematic representation of the microRNAs and their respective expression levels, putative targets and pathways involved in the development of brain arteriovenous malformations. The microRNAs are divided according to the location wherein they were identified: brain endothelial cells, vascular smooth muscle cells, or peripheral blood. An upward pointing transparent arrow signifies upregulation; a downward pointing transparent arrow denotes downregulation. Abbreviations (in alphabetical order): Akt, protein kinase B; BAVM, brain arteriovenous malformation; BMP4, bone morphogenetic protein; EC, endothelial cell; ERK, extracellular signal-regulated kinase; HIF-1A; hypoxia inducible factor 1α; Id-1, inhibitor of DNA-binding protein A; miR, microRNA; NFkB, nuclear factor kappa-light-chain of activated B cells; p38MAPK, p38 mitogen-activated protein kinase; PAI-1, plasminogen activator inhibitor 1; PI3K, phosphoinositide 3-kinase; TSP-1, thrombospondin 1; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cell.

Figure 3

Diagram indicating the microRNAs and their respective expression levels, putative targets (marked by red crosshairs) and pathways involved in the development of cerebral cavernous malformations. The microRNAs are divided according to the model in which their expression was determined: (A)—mouse models (in vivo); (B)—human brainstem (according to the genome-wide association study by Kar et al. [97]). An upward pointing transparent arrow signifies upregulation; a downward pointing transparent arrow denotes downregulation. Abbreviations (in alphabetical order): BEC, brain endothelial cell; CAND2, cullin associated and neddylation dissociated 2; CCM, cerebral cavernous malformation; ENG, endoglin; HES1, Hes family bHLH transcription factor 1; HIF-1A; hypoxia inducible factor 1α; HMGA2, high-mobility group AT-hook 2; MAPK1, mitogen-activated protein kinase 1; MIB1, mindbomb E3 ubiquitin protein ligase 1; miR, microRNA; NVU, neurovascular unit; OCLN, occludin; PDCD10, programmed cell death 10; TJP1, tight junction protein 1; VE-cadherin, vascular endothelial cadherin.