Axl, A Receptor Tyrosine Kinase, Mediates Flow-Induced Vascular Remodeling

Abstract

Intima-media thickening (IMT) in response to hemodynamic stress is a physiological process that requires coordinated signaling among endothelial, inflammatory, and vascular smooth muscle cells (VSMC). Axl, a receptor tyrosine kinase, whose ligand is Gas6, is highly induced in VSMC after carotid injury. Because Axl regulates cell migration, phagocytosis and apoptosis, we hypothesized that Axl would play a role in IMT. Vascular remodeling in mice deficient in Axl (Axl^−/−) and wild-type littermates (Axl^+/+) was induced by ligation of the left carotid artery (LCA) branches maintaining flow via the left occipital artery. Both genotypes had similar baseline hemodynamic parameters and carotid artery structure. Partial ligation altered blood flow equally in both genotypes: increased by 60% in the right carotid artery (RCA) and decreased by 80% in the LCA. There were no significant differences in RCA remodeling between genotypes. However, in the LCA Axl^−/− developed significantly smaller intima+media compared with Axl^+/+ (31±4 versus 42±6×10⁻⁶ μm³, respectively). Quantitative immunohistochemistry of Axl^−/− LCA showed increased apoptosis compared with Axl^+/+ (5-fold). As expected, p-Akt was decreased in Axl^−/−, whereas there was no difference in Gas6 expression. Cell composition also changed significantly, with increases in CD45⁺ cells and decreases in VSMC, macrophages, and neutrophils in Axl^−/− compared with Axl^+/+. These data demonstrate an important role for Axl in flow-dependent remodeling by regulating vascular apoptosis and vascular inflammation.