Rationale Abdominal aortic aneurysm (AAA) is a focal dilation of the abdominal aorta that progresses to rupture, which is frequently fatal. The only existing treatments are high risk surgical interventions. These are not offered until the AAA is large (>5.5?cm) so patients remain under surveillance for many years. There is currently no medical therapy to offer. We have previously observed a senescent phenotype in vascular smooth muscle cells (VSMC) isolated from end-stage human AAA. We hypothesise that there is a prior period of pathological VSMC remodelling which may be a promising and novel target for molecular therapies.
Methodology Three murine models of early AAA were used – (i) AngII infusion to ApoE-/- mice and (ii) CaCl2 or (iii) porcine pancreatic elastase application to the aortic adventitia of C57BL6/J mice. VSMC remodelling was investigated in fixed and paraffin embedded aortic tissue harvested from the murine models using the histochemical stain Movat’s Pentachrome and immunohistochemistry for the VSMC identification marker, αSMA. Slides were imaged with a digital slide scanner or confocal microscopy as appropriate. Aortic lumen volume was determined by in-vivo ultrasound.
Results We observed VSMC remodelling in all three models of AAA. The remodelling was reduced by administration of a novel small-molecule inhibitor of PDGF induced VSMC remodelling. Inhibition of VSMC remodelling also reduced the severity of the aneurysms formed as assessed by 3D in-vivo ultrasound of the aortic lumen.
Conclusions There is a major VSMC remodelling response in murine AAA and disrupting this response appears to suppress AAA formation.
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