Popliteal artery aneurysm (PAA) is the most frequent peripheral aneurysm, primarily seen in male smokers with a prevalence below 1%. This exploratory study aims to shed light on cellular mechanisms involved in PAA progression. Sixteen human PAA and eight non-aneurysmatic popliteal artery samples, partially from the same patients, were analyzed by immunohistochemistry, fluorescence imaging, Affymetrix mRNA expression profiling, qPCR and OLink proteomics, and compared to atherosclerotic (n = 6) and abdominal aortic aneurysm (AAA) tissue (n = 19). Additionally, primary cell culture of PAA-derived vascular smooth muscle cells (VSMC) was established for modulation and growth analysis. Compared to non-aneurysmatic popliteal arteries, VSMCs lose the contractile phenotype and the cell proliferation rate increases significantly in PAA. Array analysis identified APOE higher expressed in PAA samples, co-localizing with VSMCs. APOE stimulation of primary human PAA VSMCs significantly reduced cell proliferation. Accordingly, contractile VSMC markers were significantly upregulated. A single case of osseous mechanically induced PAA with a non-diseased VSMC profile emphasizes these findings. Carefully concluded, PAA pathogenesis shows similar features to AAA, yet the mechanisms involved might differ. APOE is specifically higher expressed in PAA tissue and could be involved in VSMC phenotype rescue.

Introduction: Popliteal artery aneurysm (PAA) is an individually highly fatal disease, causing ischemia and eventual major amputation, mainly in 50-70-year-old males. It is the most frequent peripheral artery aneurysm and correct treatment is challenging for clinicians, since both open and endovascular repair have only modest success rates, depending on the clinical presentation. In comparison to other aneurysm entities, little is known about its specific pathogenesis. Material and Methods: 26 Human PAA and popliteal artery samples were analyzed by immunohistochemistry, mRNA and miRNA expression analysis and targeted proteomics (OLink platform) to identify key features of the disease and crucial pathways involved. Additionally, a primary cell culture of PAA specimen was established for in-vitro vascular smooth muscle cell (VSMC) modulation. Results: VSMCs lose their contractile phenotype along with significant inflammatory and proteolytic changes in the vessel wall architecture. Extensive tissue remodeling with high cell turnover rates (as indicated by Ki67+ cells) compared to non-diseased popliteal artery is a unique feature in comparison to AAA. This correlates with highly abundant co-expression of the apolipoproteins E and CI with Ki67 in VSMCs in double immune-fluorescent stains. Stimulation of VSMCs with external APOE or APOCI alters proliferation rates and significantly changes a subset of contractile markers proteins upon gene expression analysis. These findings are emphasized by a specific case of a solely mechanically induced PAA in a young male. Conclusion: Pathogenesis of PAA shows similar histologic features than AAA, yet differs in key pathways involved. Increased cell turnover in the aneurysm neck area suggests evaluation of alternative treatment strategies, i.e., targeting key processes of pathogenesis such as angiogenesis and cell turnover.