Targeting pathological vascular smooth muscle cell remodelling to develop new therapeutics for abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a silent but progressive disease with no pharmacological treatment. Available treatment options – open surgical and endovascular repair carry significant risks. We hypothesize that vascular smooth muscle cell (VSMC) remodelling driven by platelet derived growth factor (PDGF) may contribute to AAA pathogenesis which could be targeted for pharmacological therapy. We used transgenic models to understand this pathological VSMC remodelling in aortic disease. We demonstrated SMC (spatial) and tamoxifen-inducibility (temporal) specificity of the Cre-recombination in our transgenic lines and set-up the porcine pancreatic elastase (PPE)-AAA model in our animal facility. Lineage tracing studies in PPE-AAA showed an increase in lineage traced SMC number and reduced expression of classical SMC markers indicating VSMC dedifferentiation with subsequent re-differentiation and healing. SM22CrePDGFRβD849V mice developed generalised aortopathy from 4 weeks. Transcriptomic analysis of aortic tissue showed 2721 differentially expressed genes mapped to important signalling pathways and cellular processes including extracellular matrix homeostasis and inflammation. Using quantitative RT-PCR, we confirmed the upregulation of key AAA-related genes Mmp2, Mmp12, Timp1, Clec3b, and Spp1 and inflammation-related genes Bmp2 and Ccr5 in SM22CrePDGFRβD849V aorta. While the (inducible) SM-MHCCreERT2PDGFRβD849V mice did not develop any major aortic phenotype, following PPE application, AAA development was similar at 14 days but then became significantly larger and progressive compared to SM-MHCCreERT2PDGFRβWT littermates. Store-operated calcium entry (SOCE) was enhanced in PDGFRβD849V VSMC compared to littermate controls and inhibited by the small molecule Orai1 inhibitor, JPIII. In vivo administration of JPIII failed to alter the progression of PPE-AAA in SM-MHCCreERT2PDGFRβD849V mice. However, Orai1 genetic deletion in SM22CrePDGFRβD849V mice partially rescued the aortic dilatation. In conclusion, these data suggest VSMC remodelling driven by PDGFR is involved in AAA development and progression and Orai1/SOCE may be a potential downstream target for therapeutics.