Blocking Signaling Pathways Like Notch and Hedgehog Reduces Neointima Formation in a Murine Aortic Transplant Model

Background: Cardiac allograft vasculopathy (CAV) remains a primary contributor to chronic rejection following heart transplantation. CAV is characterized by the formation of a neointima in the coronary vessels resulting from immune cell infiltration and smooth muscle cells (SMCs) proliferation leading to luminal occlusion and finally to tissue ischemia within the transplanted organ. A combination of effects including immunological and nonimmunological factors contributes to the development of CAV. Here, the Notch and Hedgehog signaling pathways may be involved. Antagonists blocking these pathways are available. DAPT serves as a gamma- secretase inhibitor known to disrupt the Notch signaling pathway. LDE225, as a Hedgehog pathway inhibitor, has the potential to reduce pathway activation in transplanted coronary vessels.

The main objective of this study is to investigate whether LDE225 and/or DAPT can significantly reduce neointima formation in a mouse aortic transplant model and act as potential targets to prevent CAV after cardiac transplantation.

Methods: Allogeneic thoracic aortas from C57BL/6 mice (H2b) were transplanted into the abdominal aorta of CBA mice (H2k). The study included one control group and two treatments groups (LDE225 and DAPT) each consisting of 8 animals. A gender balance was ensured in the experimental groups. Daily oral application of LDE225 or DAPT started on the first day postsurgery and was continued consistently for 29 consecutive days. On day 30, the grafts were obtained for histological examination.

Results: Histological analysis on day 30 after transplantation (Tx) showed that both LDE225 and DAPT significantly reduce chronic rejection. Murine aortic grafts treated with LDE225 showed significantly decreased neointima formation compared to control allografts (33.76% ± 13.50% vs. 50.80% ± 33.12%; p = 0.006). In DAPT treated murine aortic grafts a significantly reduced vessel occlusion was observed as compared to control allografts (28.23% ± 13.08% vs. 50.80% ± 33,12%; p = 0.001).

Conclusion: These data suggest that both Notch and Hedgehog pathway blockade seem to be promising tools to prevent the development of CAV. Our study has shown that neointima formation can be significantly attenuated in the mouse aortic transplant model offering innovative approaches for the prevention and management of CAV. Further analysis for underlying mechanisms are under progress.

 

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Artikel online veröffentlicht:
13. Februar 2024