Description
Aortic remodeling is a cause and consequence of hypertension. It increases workload on the heart and enhances arterial pulsatility in the microcirculation. We have shown that excessive endothelial stretch leads to release of Growth Arrest Specific 6 (GAS6), which in turn activates the tyrosine kinase receptor Axl on monocytes, and causes immune activation and inflammation. We hypothesized that GAS6/Axl blockade would reduce renal and vascular inflammation and lessen renal dysfunction in the setting of chronic aortic remodeling. We characterized a model aortic remodeling in mice following a 2-week infusion of angiotensin II (ang II).; Aortas demonstrated increased mural collagen and mechanical testing revealed a marked loss of Windkessel function or energy storage that persisted for 6 months following ang II. Renal function studies showed a reduced ability to excrete a volume load, a progressive increase in albuminuria and tubular damage as estimated by Periodic Acid Schiff (PAS) staining. Treatment with the Axl inhibitor R428 beginning 2 months after ang II infusion had minimal effect on aortic remodeling 2 months later, but reduced the infiltration of T cells, g/d T cells and macrophages into the aorta and kidney, and improved renal excretory capacity, reduced albuminuria, and reduced evidence of renal tubular damage. We conclude that brief episodes of hypertension can induce chronic aortic remodeling which in turn associates with a low-grade inflammation of the aorta and kidneys and evidence of renal dysfunction. These events are mediated at least in part by GAS6/Axl signaling and are improved with Axl blockade.
Overall Design
Comparative gene expression profiling analysis of RNA-seq data aortas 2, 4 and 6 months after a 2 week episode of hypertension
Curator
yq_pan