Intracranial aneurysm pathogenesis
Until now, the exact etiology of intracranial aneurysms formation remains unclear.
In addition to ambiental factors (smoking, excessive alcohol consumption and hypertension), epidemiological studies have demonstrated a familiar influence contributing to the pathogenesis of intracranial aneurysms, with increased frequency in first- and second-degree relatives of people with subarachnoid hemorrhage.
Data suggest that macrophage-derived Matrix metalloproteinase 2 and Matrix metalloproteinase 9, may play an important role in the progression of intracranial aneurysms. The findings will shed a new light into the pathogenesis of cerebral aneurysms and highlight the importance of inflammatory response causing the degeneration of extracellular matrix in the process of this disease 3).
Investigations strongly suggest that the pathophysiology is closely associated with chronic inflammation in vascular walls. Nuclear factor kappaB (NF-kappaB) has a key role in the formation and progression.
Children with Sickle Cell Disease (SCD) are at risk for developing multiple intracranial aneurysms, and a high index of suspicion must be maintained during the interpretation of routine magnetic resonance imaging or angiography of the brain 4).
Dental bacterial DNA can be found using a quantitative polymerase chain reaction in both ruptured and unruptured aneurysm walls, suggesting that bacterial DNA plays a role in the pathogenesis of cerebral aneurysms in general, rather than only in ruptured aneurysms 5).
THSD1 in Intracranial aneurysm pathogenesis
Thrombospondin type-1 domain-containing protein 1 is a protein that in humans is encoded by the THSD1 gene.
The protein encoded by this gene contains a type 1 thrombospondin domain, which is found in thrombospondin, a number of proteins involved in the complement pathway, as well as extracellular matrix proteins. Alternatively spliced transcript variants encoding distinct isoforms have been observed.
As illustrated by THSD1 research, cell adhesion may play a significant role in IA 6).
A study discovered that harmful variants in THSD1 (Thrombospondin type-1 domain-containing protein 1) likely cause intracranial aneurysm and subarachnoid hemorrhage in a subset of both familial and sporadic patients with supporting evidence from two vertebrate models 7).
A report identified THSD1 mutations in familial and sporadic IA patients and shows that THSD1 loss results in cerebral bleeding in 2 animal models. This finding provides new insight into IA and subarachnoid hemorrhage pathogenesis and provides new understanding of THSD1 function, which includes endothelial cell to extracellular matrix adhesion 8).
Toll‑like receptor (TLR) 2/4 serves an important regulatory role in nerve tissue injury. However, the downstream and potential mechanisms remain to be elucidated. The present study was designed to investigate the roles of the TLR2/4‑major myeloid differentiation response gene 88 (MyD88)‑NF‑κB signaling pathway in the development of an intracranial aneurysm. The expression of TLR2, TLR4, and MyD88 in the blood of normal controls and patients with intracranial aneurysms were detected by quantitative PCR and ELISA. Human brain vascular smooth muscle cells were treated by Angiotensin II (Ang II) to evaluate the involvement of the TLR2/4‑MyD88‑NF‑κB signaling pathway in the process. The in vitro experiment was divided into four groups: The control group, an Ang Ⅱ group, an Ang Ⅱ + small interfering (si)RNA control group, and an Ang Ⅱ + TLR2‑group. Cell viability, migration, apoptosis, and expression of TLR2, TLR4, MyD88, NF‑κB, and phosphorylated (p‑)p65 expression was detected. The results demonstrated that the expression of TLR2, TLR4, MyD88, and NF‑κB at mRNA and protein levels in patients with an intracranial aneurysm was significantly higher compared with corresponding protein in normal controls (P<0.05). <em>In vitro</em> experiments demonstrated that Ang Ⅱ treatment increased the cell proliferation and migration rate but reduced the apoptotic rate compared with the control (P<0.05). The expression of TLR2, TLR4, MyD88, NF‑κB, and p‑p65 was significantly increased in the Ang II group (vs. control; P<0.05). By contrast, TLR2‑short interfering RNA reduced the cell proliferation and migration rate and reduced the expression of TLR2, TLR4, MyD88, NF‑κB, and p‑p65 (vs. Ang Ⅱ + short interfering RNA control; P<0.05). In conclusion, the data of the present study indicated that the TLR2/4‑MyD88‑NF‑κB signaling pathway is involved in the intracranial aneurysm pathogenesis 9).