Differential Gene Expression in Coiled versus Flow-Diverter-Treated Aneurysms: RNA Sequencing Analysis in a Rabbit Aneurysm Model

Abstract

Introduction The biological mechanisms leading to aneurysm healing or rare complications such as delayed aneurysm ruptures after flow-diverter placement remain poorly understood. We used RNA-sequencing (RNA-seq) following implantation of coils or flow-diverters in elastase aneurysms in rabbits to identify genes and pathways of potential interest. Methods Aneurysms were treated with coils (n=5) or flow-diverters (n=4) or left untreated for controls (n=6). Messenger RNA were isolated from the aneurysms at 4 weeks following treatment. RNA samples were processed using RNA-seq technology and analyzed using the Ingenuity Pathway Analysis tool. Results Using RNA-seq for coiled versus untreated aneurysms, 464/9990 genes (4.6%) were differentially expressed (58 down-regulated, 406 up-regulated). Comparing flow-diverter versus untreated aneurysms, 177/10041 (1.8%) genes were differentially expressed (8 down-regulated, 169 up-regulated). Comparing flow-diverter versus coiled aneurysms, 13/9982 (0.13%) genes were differentially expressed (8 down-regulated, 5 up-regulated). Keratin 8 was overexpressed in flow-diverters versus coils. This molecule may potentially play a critical role in delayed ruptures due to plasmin production. We identified overregulation of apelin in flow-diverters supporting the preponderance of endothelialization, whereas we found overexpression of molecules implicated in wound healing (Dectin1 and HHIP) for coiled aneurysms. Furthermore, we identified metallopeptidases 1, 12 and 13 as overexpressed in coiled versus untreated aneurysms. Conclusions We observed different physiopathologic responses after endovascular treatment with different devices. Flow-diverters promote endothelialization but express molecules that could potentially explain the rare delayed ruptures. Coils promote wound healing and express genes potentially implicated in recurrence of coiled aneurysms.

Mechanism of Action and Biology of Flow Diverters in the Treatment of Intracranial Aneurysms

“…Previous work from our group evaluating gene expression following flow diverter treatment using RNA sequencing technology has shown substantial differences in gene expression profiles in coiled vs flow diverter-treated aneurysms. 33 Compared with untreated aneurysms, key genes involved in endothelial function including apelin and CXCL-8 were upregulated in flow diverter-treated aneurysms. Additionally, a large number of upregulated gene expression in flow diverter are oriented toward mitogenic activity and cell cycle progression (cyclin B2 cyclin-dependent kinase 1 [cyclin B1] among others).…”

Topographic distribution of inflammation factors in a healing aneurysm

“…Regarding different EVT, it is interesting to note that the expression of inflammation factors varies substantially between conventional coil embolization and flow diverter (FD) treatment. Specifically, in experimental rabbit aneurysms, molecules associated with wound healing were found four times more often in coiled aneurysms than following FD treatment [ 22 ]. This suggests that aneurysm healing after coiling depends predominantly on intra-aneurysmal thrombus organization, whereas healing after FD depends rather on direct endothelial cell proliferation along the scaffold, of cells originating predominantly from the parent artery (and potentially circulating progenitor cells) [ 1 , 2 ].…”

Topographic Distribution of Inflammation Factors in a Healing Aneurysm

“…Speci cally, in experimental rabbit aneurysms, molecules associated with wound healing were found four times more often in coiled aneurysms than following FD treatment. [20] This suggests that aneurysm healing after coiling depends predominantly on intra-aneurysmal thrombus organization, whereas healing after FD depends rather on direct endothelial cell proliferation originating from the parent artery. [1,2] Furthermore, genes related to in ammation (TNF-a, monocyte chemoattractant protein 1) were upregulated, whereas proteinases (MMP 2 and 9) and structural proteins (collagens and bronectin) were expressed at lower levels in FD treatment compared with coiled aneurysms.…”