Significant induction of PD-ECGF and E-selectin in remodeled tunica media of thoracic aortic aneurysm and dissection tissues indicates a preventive effect of cimetidine

Introduction: Aortic aneurysms and dissections are the most common pathologic alterations in thoracic aortic disease. The mortality rate following aortic rupture is as high as 65−85%. Therefore, a preventive approach for aneurysm disease is of highest clinical impact. Basis for the development of a preventive pharmacologic therapy is the knowledge of histopathological processes leading to loss of biomechanical stability of the aortic wall. Markers such as PD-ECGF (platelet-derived endothelial cell growth factor) or E-selectin accompany and cause the pathological induction or media remodeling. Treatment of a rat dissection model with cimeditine targeting PD-ECGF, resulted in increased survival rate by suppression of rupture.

Study aim was to monitor PD-ECGF and E-selectin expression in aortic patient samples. Correlation of expression with disease status and localization of neoangiogenesis in the tunica media indicate the purpose of a cimetidine application to prevent or treat human thoracic aneurysm.

Methods: Aorta tissue of 19 patients were collected after surgical intervention of thoracic aortic aneurysms or dissections (TAAD), eight samples were non-TAAD controls. After formalin fixation, paraffin embedding and histological sliding (3 µm), sections were stained with picrosiriusred, HE and Elastica-van-Gieson-staining using standardized protocols. Grading was performed according to tissue remodeling pathology of the tunica media, adventitia and intima. IHC-staining was performed for angiogenesis makers PD-ECGF and E-selectin as well as immune cells positive for CD15 and CD3. E-selectin was additionally analyzed via IF-staining. Elastin content or layer dependent marker expression were manually quantified with Fiji software and related to tunica media or intima section area.

Results: Non-TAAD samples exhibit with 30.3 ± 7.1 % significant higher media elastin content than aneurysms and dissection samples (20.7 ± 9.2 % and 19.9 ± 5.8 %, respectively). Patient samples graded in score 3 exhibited with 15.1 ± 5.2 % a significant lower media elastin content than samples of score 0 (30.1 ± 6.7 %). PD-ECGF and E-selectin expression was elevated especially in areas with media remodeling also characterized by elastin fiber and SMC nuclei loss. Quantification of PD-ECGF expression in media section revealed a significant higher rate of 0.9 ± 0.9 % in patient samples of score 3 compared to score 0 with 0.2 ± 0.1 %. IF staining was performed to discriminate the expression level of intralamellar E-selectin  (859 ± 385 CTF/µm²) from the significantly higher expression in remodeled media substructures (1361 ± 649 CTF/µm²) in patient samples of scores 2 and 3. A significantly higher expression of PD-ECGF in the intima was verified in the subset of samples in pathological intima scores 2 and 3. Immune CD15 and CD3 positive cells were monitored in the tunica media remodeled areas positive also for PD-ECGF and E-selectin.

Conclusion: PD-ECGF and E-selectin expression is significantly induced in pathological aortic tissues with intense tissue remodeling compared to non-TAAD aorta. In addition, in this localization pathology related inflammatory cells are present. These results indicate the potential preventive effect of cimetidine for aneurysm formation.