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intracranial_aneurysm_pathophysiology

Intracranial aneurysm pathophysiology

The development of intracranial aneurysm is related to hemodynamics stress.

Alterations in the internal elastic membrane (lamina elastica interna) of cerebral arteries are thought to weaken vessel walls and render them less resistant to changes in intraluminal pressure 1).

These changes most frequently develop at sites of vessel bifurcation, where blood flow is most turbulent and shear forces against the arterial wall are greatest 2).

This can be because of acquired disease or hereditary factors. The repeated trauma of blood flow against the vessel wall presses against the point of weakness and causes the aneurysm to enlarge. As described by the Law of Young-Laplace, the increasing area increases tension against the aneurysmal walls, leading to enlargement.

Despite evidence for a potential role of angiotensin in the pathophysiology, angiotensin-receptor blockers have shown little-to-no efficacy in preventing aneurysm formation and growth 3).

Despite technical and diagnostic progress there are still open questions in the understanding of the pathophysiology of intracranial aneurysms.

Assuming a preexisting reduced resistibility of the vessel wall to pressure changes and an area of permanently low wall shear stress WSS, an increase in pressure induces geometrical changes. These cause changes of intravascular flow distribution, lowering the already low WSS in specific locations. This leads to endothelial damage in this area and to a decreasing stability of the vessel wall, causing aneurysm development, growth, and rupture 4).

MicroRNA and aneurysm

The molecular mechanisms behind intracranial aneurysm formation and rupture remain poorly understood.

The MicroRNA and mRNA interactions and expression levels in cerebral aneurysm tissue from human subjects were profiled.

A prospective case-control study was performed on human subjects to characterize the differential expression of mRNA and miRNA in unruptured cerebral aneurysms in comparison with control tissue (healthy superficial temporal arteries [STA]). Ion Torrent was used for deep RNA sequencing. Affymetrix miRNA microarrays were used to analyze miRNA expression, whereas NanoString nCounter technology was used for validation of the identified targets.

Overall, 7 unruptured intracranial aneurysm and 10 STA specimens were collected. Several differentially expressed genes were identified in aneurysm tissue, with MMP-13 (fold change 7.21) and various collagen genes (COL1A1, COL5A1, COL5A2) being among the most upregulated. In addition, multiple miRNAs were significantly differentially expressed, with miR 21 (fold change 16.97) being the most upregulated, and miR 143-5p (fold change -11.14) being the most downregulated. From these, miR-21, miR-143, and miR 145 had several significantly anticorrelated target genes in the cohort that are associated with smooth muscle cell function, extracellular matrix remodeling, inflammation signaling, and lipid accumulation. All these processes are crucial to the pathophysiology of cerebral aneurysms.

This analysis identified differentially expressed genes and miRNAs in unruptured human cerebral aneurysms, suggesting the possibility of a role for miRNAs in aneurysm formation. Further investigation for their importance as therapeutic targets is needed 5).

1)
Selman WR, Tarr RW, Ratcheson RA. Intracranial aneurysms and subarachnoid hemorrhage. In: Bradley WG, et al., eds. Neurology in clinical practice. 3d ed. Boston: Butterworth-Heinemann,2000:1188–90.
2)
Inci S, Spetzler RF. Intracranial aneurysms and arterial hypertension: a review and hypothesis. Surg Neurol. 2000;53:530–40.
3)
Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, et al. Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab. 2012;32:1659–1676.
4)
Doenitz C, Schebesch KM, Zoephel R, Brawanski A. A mechanism for the rapid development of intracranial aneurysms: a case study. Neurosurgery. 2010 Nov;67(5):1213-21; discussion 1221. doi: 10.1227/NEU.0b013e3181f34def. PubMed PMID: 20948398.
5)
Bekelis K, Kerley-Hamilton JS, Teegarden A, Tomlinson CR, Kuintzle R, Simmons N, Singer RJ, Roberts DW, Kellis M, Hendrix DA. MicroRNA and gene expression changes in unruptured human cerebral aneurysms. J Neurosurg. 2016 Dec;125(6):1390-1399. PubMed PMID: 26918470; PubMed Central PMCID: PMC5001931.
intracranial_aneurysm_pathophysiology.txt · Last modified: 2016/12/03 11:31 (external edit)