Significant PD-ECGF and E-selectin induction in pathological remodeling of thoracic aortic tissue - target for a preventive cimetidine strategy

Abstract Introduction Development of a preventive treatment strategy against aortic aneurysms progression is of highest clinical impact since the mortality rate is 65-85 % following aortic rupture. Knowledge of the histopathological processes in the dilatated aortic wall leading to biomechanical instability is needed to develop a pharmacologic therapy. PD-ECGF (platelet-derived endothelial cell growth factor) or E-selectin expression accompany media remodeling. PD-ECGF induces matrix metalloproteinase 2 (MMP2). Cimeditine treatment of a rat dissection model targeting PD-ECGF, resulted in increased survival rate by suppression of aortic rupture. Purpose Study aim was to monitor PD-ECGF, E-selectin and MMP2 expression in patient aortic samples. Correlation of expression with disease status and localization of neoangiogenesis in the tunica media indicate the purpose of a cimetidine application to prevent thoracic aneurysm. Methods Aorta tissue of 19 patients were collected after surgical intervention of thoracic aortic aneurysms or dissections (TAAD; eight non-TAAD controls EK268062016). After formalin fixation, paraffin embedding and histological sliding, sections were stained with picrosiriusred, HE and Elastica-van-Gieson-staining using standardized protocols. Grading was performed according to tissue remodeling pathology. IHC-staining was performed for angiogenesis makers PD-ECGF, E-selectin and MMP2 as well as immune cells (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 layer section area. Results TAAD exhibit with 20.7 ± 9.2 % and 19.9 ± 5.8 %, respectively, a significant lower elastin content than non-TAAD samples (30.3 ± 7.1 %). Grade 3 samples revealed with 15.1 ± 5.2 % a significant lower media elastin content than score 0 (30.1 ± 6.7 %). PD-ECGF and E-selectin expression was elevated especially in remodeled media loci with elastin fiber disorganization or loss. PD-ECGF expression in the TAAD samples correlates with the patient aortic diameter (p=0.034). Also, MMP2 expression in remodeled media was detected with inhomogeneous pattern in an initial subset. A significantly higher expression of PD-ECGF in the intima was verified in pathological intima scored 2 and 3. Intralamellar E-selectin expression in IF staining was with 1361 ± 649 CTF/µm2 significantly higher in remodeled media substructures in patient samples of scores 2 compared to non-remodeled areas 3859 ± 385 CTF/µm2. Immune CD15 or 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 media remodeling compared to non-TAAD. This is associated with MMP2 expression, correlates to patient aorta diameter and indicates the potential preventive cimetidine effect for aneurysm formation.