YAP/TAZ Signaling in Endothelial Cells Mediates the Pathogenesis of Abdominal Aortic Aneurysm Formation

Background

Abdominal aortic aneurysms (AAA) are characterized by dilation of the aorta that can lead to aortic rupture and death. The transcriptional co-activators Yes-Associated Protein (YAP) and WW-domain-containing transcriptional co-activator with PDZ-binding motif (TAZ) are mechanosensitive effectors of the highly conserved Hippo signaling pathway. It is hypothesized that cell-specific YAP/TAZ signaling in endothelial cells (EC) plays a pivotal role in mediating AAA formation and rupture.

Methods

Single-cell RNA-sequencing in human AAAs was performed and differentially expressed genes (DEGs) were identified in the endothelial cell cluster. YAP/TAZ mRNA and protein expression were also assessed in human AAA and control aortic tissue. Two established murine AAA models were used with male C57BL/6 and EC-CreER ^{T 2} -YAP ^fl/fl /TAZ ^fl/fl mice with/without Verteporfin (VPF, YAP/TAZ inhibitor) and XMU-MP-1 (YAP/TAZ activator) treatments. On postoperative days 14 and 28, aortic diameter, histology, cytokine, and MMP2 expressions were evaluated.

Results

A significant alteration in EC-specific differentially expressed YAP/TAZ-related genes was observed in which 242 genes were upregulated and 71 genes were downregulated in AAA compared to controls. Human AAA tissue showed a significant increase in YAP and TAZ protein expressions compared to controls. Elastase-treated EC-YAP/TAZ ^-/- mice showed a significant decrease in AAA diameter compared to littermate controls. Histological quantification revealed preservation of α-smooth muscle actin, reduced elastin fiber breaks, and decreased macrophage infiltration in EC-YAP/TAZ ^-/- mice compared to littermate controls. Importantly, pharmacological inhibition of YAP/TAZ using VPF significantly attenuated AAAs in two experimental murine models. In vitro data demonstrates that VPF inhibits endothelial cell YAP expression, downregulating pathways associated with pathogenic angiogenesis and vascular inflammation.

Conclusions

These data suggest that EC-specific YAP/TAZ signaling mediates AAA formation. Pharmacological inhibition of the Hippo pathway can significantly mitigate aortic inflammation and vascular remodeling to decrease the progression of AAAs and prevent aortic rupture.

Highlights

• Expression of YAP/TAZ in endothelial cells is dysregulated in human AAAs.

• Experimental murine models demonstrate that: a) endothelial-cell specific deletion of YAP/TAZ protects against AAA formation, and pharmacologic alteration with b) verteporfin attenuates AAA formation, and c) XMU-MP-1 significantly exacerbates aortic inflammation, vascular remodeling, and rupture.

• Verteporfin inhibits endothelial YAP/TAZ activation by modulating ECM remodeling, pathogenic angiogenesis, pro-inflammatory cytokine and chemokine expression.