Abstract Body: Objectives: Abdominal aortic aneurysms (AAA) are pathologic dilations that can lead to rupture. Yes-Associated Protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) are mechanosensitive effectors of the Hippo signaling pathway. We hypothesize that cell-specific YAP/TAZ signaling in endothelial (EC) and smooth muscle cells (SMCs) plays a pivotal role in AAA formation.

Methods: Human AAA and control samples were analyzed using a publicly available sc-RNA seq dataset (GSE166676). Human YAP/TAZ mRNA and protein expression were assessed with qRT-PCR and western blot. Two murine AAA models were used: 1) 14-day topical elastase and 2) 28-day β-aminopropionitrile (BAPN) + topical elastase. Male C57BL/6 mice were treated (i.p.) with verteporfin (VPF, 50mg/kg, YAP/TAZ inhibitor), XMU-MP-1 (3mg/kg, YAP/TAZ activator), or vehicle control (0.2 ml saline). Smmhc-CreER^T2-YAP/TAZ^fl/fl and EC-CreER^T2-YAP/TAZ^fl/fl cell-specific knockout models underwent 14-day topical elastase induction. Aortas were harvested for histology, cytokines, and MALDI analysis. Statistical analysis was performed by students t-test with Mann Whitney correction (p<.05).

Results: Thirty-three YAP/TAZ-related SMC differentially expressed genes were identified in AAA samples (Figure 1). TAZ mRNA (2.3±.4; n=16; p=.01) and YAP (3.2±1.1; n=6-7; p<.05) / TAZ (3.7±1.0; n=6-7; p<.01) protein expression were upregulated in human AAA. XMU-MP-1 increased AAAs in 14-day (181±43 vs. 130±26; n=20-26; p<.0001) and 28-day models (365±51 vs. 258±43; n=6-7; p<.01) compared to controls. VPF treatment attenuated AAAs in 14-day (82±32 vs. 142±23; n=20-24; p<.0001) and 28-day models (186±64 vs. 265±106; n=17-23; p<.01), and reduced MCP-1, IL-6, and MMP2 expression (n=5; p<.01). Smmhc-CreER^T2-YAP/TAZ^fl/fl mice exhibited larger AAAs (221±53 vs. 155±13; n=20-26; p<.0001), while EC-CreER^T2-YAP/TAZ^fl/fl AAAs were smaller (112±29 vs. 161±42; n=13-15; p<.01) compared to littermate controls. Greater elastic fiber disruption, macrophage infiltration, and metabolic upregulation of molecules involved in oxidative stress and inflammation were seen in SMC KO mice on histologic and MALDI analysis.

Conclusions: YAP/TAZ signaling in AAA formation may be pharmacologically altered and serve diverging roles based on cell type. Ongoing investigations are focused on delineating the Hippo pathway mediators to further elucidate EC and SMC crosstalk in YAP/TAZ-mediated signaling during AAA formation.