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. 2023 Aug 2;20(1):182.
doi: 10.1186/s12974-023-02863-1.

Topographic distribution of inflammation factors in a healing aneurysm

Basil E Grüter  1   2   3 , Gwendoline Canzanella  4   5 , Joshua Hägler  4   5 , Jeannine Rey  4   5 , Stefan Wanderer  4   5 , Michael von Gunten  5   6 , José A Galvan  7 , Rainer Grobholz  8   9 , Hans-Rudolf Widmer  5 , Luca Remonda  10   5 , Lukas Andereggen  4   5 , Serge Marbacher  4   5
Affiliations

Topographic distribution of inflammation factors in a healing aneurysm

Basil E Grüter et al. J Neuroinflammation. .

Abstract

Background: Healing of intracranial aneurysms following endovascular treatment relies on the organization of early thrombus into mature scar tissue and neointima formation. Activation and deactivation of the inflammation cascade plays an important role in this process. In addition to timely evolution, its topographic distribution is hypothesized to be crucial for successful aneurysm healing.

Methods: Decellularized saccular sidewall aneurysms were created in Lewis rats and coiled. At follow-up (after 3 days (n = 16); 7 days (n = 19); 21 days (n = 8)), aneurysms were harvested and assessed for healing status. In situ hybridization was performed for soluble inflammatory markers (IL6, MMP2, MMP9, TNF-α, FGF23, VEGF), and immunohistochemical analysis to visualize inflammatory cells (CD45, CD3, CD20, CD31, CD163, HLA-DR). These markers were specifically documented for five regions of interest: aneurysm neck, dome, neointima, thrombus, and adjacent vessel wall.

Results: Coiled aneurysms showed enhanced patterns of thrombus organization and neointima formation, whereas those without treatment demonstrated heterogeneous patterns of thrombosis, thrombus recanalization, and aneurysm growth (p = 0.02). In coiled aneurysms, inflammation markers tended to accumulate inside the thrombus and in the neointima (p < 0.001). Endothelial cells accumulated directly in the neointima (p < 0.0001), and their presence was associated with complete aneurysm healing.

Conclusion: The presence of proinflammatory cells plays a crucial role in aneurysm remodeling after coiling. Whereas thrombus organization is hallmarked by a pronounced intra-thrombotic inflammatory reaction, neointima maturation is characterized by direct invasion of endothelial cells. Knowledge concerning topographic distribution of regenerative inflammatory processes may pave the way for future treatment modalities which enhance aneurysm healing after endovascular therapy.

Keywords: Animal; Endovascular procedures; Inflammation; Intracranial aneurysm; Models; Neointima.

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Conflict of interest statement

There are no competing interests of any of the authors.

Figures

Fig. 1
Fig. 1
Study design flowchart. Of a total of n = 52 animals, n = 5 were used as tissue donors and n = 4 were excluded due to morbidity (n = 2, postoperative paraplegia) or premature mortality (n = 2: n = 1 anesthesia related, n = 1 unclear). No 21-day follow-ups were performed in the control group as the model is associated with high rates of aneurysm growth and spontaneous rupture in this timeframe [4]
Fig. 2
Fig. 2
Evolution of aneurysm healing without and with coil treatment. Longitudinal cuts of the aneurysm complex following natural course (top row) and coil (*) treatment (bottom row), 3 days (A, C), 7 days (B, D) and 21 days (E) into the healing process. Note the absence of cells in the aneurysm wall. After 3 days of coil treatment (C) there is already a small tissue layer, separating the lumen of the adjacent vessel (AV) from the early hematoma (H) in the aneurysm sac, which develops into a thick neointima (N). Early hematoma is gradually transformed (D) into mature thrombus (T) with only minimal residual hematoma in the top part of the aneurysm sac after 3 weeks (E). In the absence of coils, the intra-aneurysmal hematoma shows massive neutrophile invasion, insufficient thrombus maturation and remaining central residual aneurysm perfusion (B)
Fig. 3
Fig. 3
Aneurysm healing reflected by neointima formation as a function of treatment (coiling) and time. No relevant difference between coiled and uncoiled aneurysms was found at three days post-op. However, after seven days those with coil treatment showed significantly stronger neointima formation. Good aneurysm healing reflected by strong neointima formation was confirmed in the replication cohort (FU 7 days) and in the long-term cohort (FU 21 days). *p < 0.05
Fig. 4
Fig. 4
Timely evolution of humoral and cellular inflammation and aneurysm healing after coil treatment. The bar diagrams show median and interquartile range for humoral (panels A and B) and cellular (panels C and D) inflammation. Cross-sectional data from different animals over time suggest that humoral inflammation peaks at Day 7 for most factors—predominantly in the thrombus and neointima, and to a lesser extend in the aneurysm wall (panels A and B). On a cellular level (panels C and D), inflammation cells accumulate in the thrombus, but not in the aneurysm wall. Delayed (after Day 7) increase of VEGF corresponds with increasing endothelialization (CD 31) and thus complete healing over time (p = 0.01). *p < 0.05
Fig. 5
Fig. 5
Schematic representation of topographical patterns in a healing aneurysm. Overall, most factors (i.e., MMP2, MMP9, FGF) and cell types (CD163, CD3, HLA-DR) showed the highest accumulation in the neointima followed by the thrombus compartment but were neglectable in the aneurysm wall and in the adjacent vessel (A). Few factors (TNF-α, Il6) were equally distributed among the neointima and the thrombus (B). The accumulation of B cells (CD20) was higher in the thrombus than in the neointima and scarcely any B cells were found in the adjacent vessel wall (C). Lastly, endothelial cells () accumulate directly in the neointima, and their presence is associated with complete aneurysm healing
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