Inhibition of pathologic angiogenesis in thoracic aortic aneurysms and dissections – new approach for a preventive therapy?

Introduction: Most common pathologic alteration in thoracic aortic disease are thoracic aortic aneurysms and dissections. Despite surgical therapy mortality of dissection still reaches up to 60 %. Therefore, a preventive approach for aneurysms disease is required. The development of strategies rely on knowledge of pathophysiological aortic tissue changes including remodeling of especially tunica media e.g. by fragmentation/loss of elastin fibers, smooth muscle cell (SMC) disorganization/nuclei loss. The induction of angiogenesis and disassembling and ingrowth of vasa vasorum in the inner aortic layers are assumed. Markers such as PD-ECGF (platelet-derived endothelial cell growth factor) or E-selectin accompany this pathological induction. Cimetidine, a histamine-2-receptor-antagonist, exhibits in vivo immunomodulatory, cell adhesion, anti-proliferative and anti-angiogenic efficacy in cancer tissues and inhibits PD-ECGF. Treatment with this substance resulted in increased survival rate by suppression of rupture in a rat dissection model. Aim of presented histological study was to monitor PD-ECGF and E-selectin expression in aortic patient samples. Verification and correlation of expression patterns with status of pathophysiological changes indicate the rationale for a potential use of cimetidine to also prevent human thoracic aneurysm.

Methods: In total 27 human thoracic aortic tissue samples were implemented. 19 of these samples were collected after surgical intervention of aortic aneurysms or dissections, eight samples were control tissues. 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 degree of pathologic aspects concerning the tunica media. Changes of tunica intima and adventitia were also monitored. In addition, samples were IHC-stained for PD-ECGF and E-selectin. Elastin content was determined and quantified with Fiji software and related to tunica media section area. PD-ECGF positivity was scored, based on the localization in the section.

Results: Grading of 19 pathological aortic samples revealed in four cases severe pathological tissue resembling of grade 3. Nine samples were grade 2 and five samples exhibit marginal changes of grade 1. Controls were classified as grade 0. Grade 3 samples exhibited with 7.8 ± 15.1 % a significant lower elastin content than samples of grade 0 (30.1 ± 6.7 %). Expression of PD-ECGF was detected in all samples in the tunica media. All pathological aortic samples with grading 3 also were classified with high expression (grade 2 or 3) of PD-ECGF, revealing an overexpression of the angiogenesis marker in these samples. Aortic tissue samples graded pathology 1 or 2 showed an intermediate media PD-ECGF expression of mean grading 1.6 and 1.8 respectively, controls reached a mean grading of 0.8 revealing a low expression. Furthermore, E-selectin expression was detected in aortic sections at least in part independent from vessel structures.

Conclusion: PD-ECGF expression is elevated in pathological aortic sections especially with intense elastin fiber remodeling compared to control. Further investigation of E-selectin, histamine receptor expression and involved inflammatory cells and correlation is envisioned to estimate the potential application of anti-angiogenetic therapeutics to inhibit aortic aneurysm progression.