Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Dec;21(4):325-343.
doi: 10.1007/s12017-019-08537-7. Epub 2019 May 4.

Intracranial Aneurysms: Pathology, Genetics, and Molecular Mechanisms

Zhen Xu  1 , Yan-Ning Rui  1 , John P Hagan  2 , Dong H Kim  3
Affiliations
Review

Intracranial Aneurysms: Pathology, Genetics, and Molecular Mechanisms

Zhen Xu et al. Neuromolecular Med. 2019 Dec.

Abstract

Intracranial aneurysms (IA) are local dilatations in cerebral arteries that predominantly affect the circle of Willis. Occurring in approximately 2-5% of adults, these weakened areas are susceptible to rupture, leading to subarachnoid hemorrhage (SAH), a type of hemorrhagic stroke. Due to its early age of onset and poor prognosis, SAH accounts for > 25% of years lost for all stroke victims under the age of 65. In this review, we describe the cerebrovascular pathology associated with intracranial aneurysms. To understand IA genetics, we summarize syndromes with elevated incidence, genome-wide association studies (GWAS), whole exome studies on IA-affected families, and recent research that established definitive roles for Thsd1 (Thrombospondin Type 1 Domain Containing Protein 1) and Sox17 (SRY-box 17) in IA using genetically engineered mouse models. Lastly, we discuss the underlying molecular mechanisms of IA, including defects in vascular endothelial and smooth muscle cells caused by dysfunction in mechanotransduction, Thsd1/FAK (Focal Adhesion Kinase) signaling, and the Transforming Growth Factor β (TGF-β) pathway. As illustrated by THSD1 research, cell adhesion may play a significant role in IA.

Keywords: Animal models; Etiology; Genetics; Intracranial aneurysm; Subarachnoid hemorrhage; THSD1.

PubMed Disclaimer

Conflict of interest statement

Compliance with Ethical Standards

There are no conflicts of interest to report.

Figures

Figure 1.
Figure 1.. Schematic of IA genes in vascular endothelial cells.
Three IA genes including THSD1, SOX17, and ARHGEF17 are highlighted in red. THSD1 physically interacts with integrin complex through talin at nascent focal adhesion. When nascent focal adhesion matures, THSD1 leaves for next nascent focal adhesion site via endosome-mediated recycling process. Loss of THSD1 leads to defects in focal adhesion, a key determinant of the actin cytoskeleton, and modulator of several downstream pathways. Sox17 functions as a transcriptional factor and modulates VE-cadherin expression. Loss of VE-cadherin decreases cell-cell adhesion and increases permeability. ARHGEF17 is guanidine exchange factor that potentially regulates the remodeling of actin cytoskeleton.
Figure 2.
Figure 2.. THSD1/FAK signaling with its downstream targets.
THSD1 is required for normal levels of focal adhesions and THSD1 loss reduces the overall amount of focal adhesions, FAK, and active phosphorylated FAK in endothelial cells. As a result, several pathways may be implicated including SRC, PI3K/AKT, Rho, and Rac1 signaling that affects actin cytoskeleton organization and cell adhesion mediated in part through integrins and mechanosensors.
See this image and copyright information in PMC

References

    1. AbouAlaiwi WA, Takahashi M, Mell BR, Jones TJ, Ratnam S, Kolb RJ, et al. (2009). Ciliary polycystin-2 is a mechanosensitive calcium channel involved in nitric oxide signaling cascades. Circ Res, 104(7), 860–869, doi:10.1161/CIRCRESAHA.108.192765. - DOI - PMC - PubMed
    1. Abrantes P, Santos MM, Sousa I, Xavier JM, Francisco V, Krug T, et al. (2015). Genetic Variants Underlying Risk of Intracranial Aneurysms: Insights from a GWAS in Portugal. [Research Support, Non-U.S. Gov’t]. PLoS One, 10(7), e0133422, doi:10.1371/journal.pone.0133422. - DOI - PMC - PubMed
    1. Akagawa H, Tajima A, Sakamoto Y, Krischek B, Yoneyama T, Kasuya H, et al. (2006). A haplotype spanning two genes, ELN and LIMK1, decreases their transcripts and confers susceptibility to intracranial aneurysms. [Research Support, Non-U.S. Gov’t]. Hum Mol Genet, 15(10), 1722–1734, doi:10.1093/hmg/dd1096. - DOI - PubMed
    1. Akiyama K, Narita A, Nakaoka H, Cui T, Takahashi T, Yasuno K, et al. (2010). Genome-wide association study to identify genetic variants present in Japanese patients harboring intracranial aneurysms. [Research Support, Non-U.S. Gov’t]. J Hum Genet, 55(10), 656–661, doi:10.1038/jhg.2010.82. - DOI - PubMed
    1. Alg VS, Ke X, Grieve J, Bonner S, Walsh DC, Bulters D, et al. (2018). Association of functional MMP-2 gene variant with intracranial aneurysms: case-control genetic association study and meta-analysis. [Multicenter Study Observational Study]. Br J Neurosurg, 32(3), 255–259, doi:10.1080/02688697.2018.1427213. - DOI - PubMed

Publication types

MeSH terms