2. Academic Validation
  3. Role of Axl in target organ inflammation and damage due to hypertensive aortic remodeling

Role of Axl in target organ inflammation and damage due to hypertensive aortic remodeling

  • Am J Physiol Heart Circ Physiol. 2022 Sep 9. doi: 10.1152/ajpheart.00253.2022.
Wei Chen 1,  Justin P Van Beusecum 2 3,  Liang Xiao 1 4,  David M Patrick 1 5,  Mingfang Ao 1,  Shilin Zhao 6,  Marcos G Lopez 7,  Frederic T Billings 4th 7,  Cristina Cavinato 8,  Alexander W Caulk 8,  Jay D Humphrey 8 9,  David G Harrison 1
Affiliations

Affiliations

  • 1 Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States.
  • 2 Ralph H. Johnson Veteran Affairs Medical Center, Charleston, SC, United States.
  • 3 Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC, United States.
  • 4 Kidney Disease Center, the First Affiliated Hospital, College of Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
  • 5 Veterans Affairs Medical Center, Nashville, TN, United States.
  • 6 Vanderbilt Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville,TN, United States.
  • 7 Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, United States.
  • 8 Department of Biomedical Engineering, Yale University, New Haven, CT, United States.
  • 9 Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, United States.
PMID: 36083796 DOI: 10.1152/ajpheart.00253.2022
Abstract

Excessive endothelial cell stretch causes release of Growth Arrest Specific 6 (GAS6), which activates the tyrosine kinase receptor Axl on monocytes and promotes 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 of aortic remodeling in mice following a 2-week infusion of angiotensin II (ang II). These mice had chronically increased pulse wave velocity and their aortas demonstrated increased mural collagen. Mechanical testing revealed a marked loss of Windkessel function 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 staining. Treatment with the Axl Inhibitor R428 beginning 2 months after ang II 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. In humans, circulating Axl+/Siglec6+ dendritic cells and phosphoAxl+ cells correlated with pulse wave velocity and aortic compliance measured by transesophageal echo, confirming chronic activation of the GAS6/Axl pathway. We conclude that brief episodes of hypertension induce chronic aortic remodeling which associates with persistent 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.

Keywords

T cells; Vascular remodeling; Windkessel Function; aorta; macrophages.

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