Upregulation of the GM-CSF/GM-CSF-receptor system in aneurysm: Trigger for structural alterations?

The granulocyte-macrophage-colony-stimulating-factor (GM-CSF), a proinflammtory cytokine, is of importance for maintenance of vascular structure. As demonstrated by genetically modified mouse models GM-CSF regulates the metabolism of collagen and elastin. GM-CSF-deficiency leads to collagen-reduction and elastin-hypertrophy. GM-CSF-overexpressing mice show reduced elastin-production. Since chronic inflammation and elastin-degradation are hallmarks of aortic abdominal aneurysms (AAA), we hypothesize that aneurysms show alterations in the expression of GM-CSF its receptor system.

Samples of AAA (N=9) and control aortas (CTRLs, N=20) were used. Samples were recruited from patients undergoing AAA-reconstruction and ACB-surgery. Expression of GM-CSF and its receptor subunits [alpha1/2 (GMRα1, GMRα2) and β (GMRβ)] were analyzed by RT-PCR and immunohistochemistry.

In CTRLs GM-CSF, GMRα1 and GMRβ are expressed, GM-CSF and GMRβ by 1/3 of GMRα1. In comparison with CTRLs, AAA-samples show 2.9-fold increased GM-CSF-levels (AAA: 1.00±0.49 vs. CTRLs: 0.34±0.21, p=0.003) and a 3.5-fold increase of GMRβ (AAA: 0.66±0.25 vs. CTRLs: 0.19±0.13, p=0.0004). GMRα1-levels are comparable to those of CTRLs (AAA: 0.93±0.29 vs. CTRLs: 0.75±0.13, p=0.13). Only two AAA-samples showed expression of GMRα2 (expressed by macrophages but not by smooth muscle cells).

Our study proves that in AAA the GM-CSF/GM-CSF-receptor system is altered. While GMRα1 is strongly expressed in both groups, GM-CSF and the GMRβ subunit are upregulated in AAA. This increase probably triggers the degradation of elastin and the remaining connective tissue in AAA. Interestingly, GMRα2 is found in few AAA samples indicating that structural degradation in AAA does not generally depend on macrophages. This modulation of GM-CSF or the GMRβ subunit may give rise to new therapeutic strategies for AAA.