Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Ralph H. Johnson Veteran Affairs Medical Center, Charleston, South Carolina.
Am J Physiol Heart Circ Physiol. 2022 Nov 1;323(5):H917-H933. doi: 10.1152/ajpheart.00253.2022. Epub 2022 Sep 9.
We have shown that 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-wk 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 mo following ANG II infusion. 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 mo after ANG II infusion had a minimal effect on aortic remodeling 2 mo later but reduced the infiltration of T cells, γ/δ 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 phospho-Axl 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 is associated 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. In this study, a brief, 2-wk period of hypertension in mice led to progressive aortic remodeling, an increase in pulse wave velocity, and evidence of renal injury, dysfunction, and albuminuria. This end-organ damage was associated with persistent renal and aortic infiltration of CD8 and γ/δ T cells. We show that this inflammatory response is likely due to GAS6/Axl signaling and can be ameliorated by blocking this pathway. We propose that the altered microvascular mechanical forces caused by increased pulse wave velocity enhance GAS6 release from the endothelium, which in turn activates Axl on myeloid cells, promoting the end-organ damage associated with aortic stiffening.
我们已经表明，内皮细胞过度拉伸会导致生长停滞特异性 6（GAS6）的释放，GAS6 会激活单核细胞上的酪氨酸激酶受体 Axl，从而促进免疫激活和炎症。我们假设，GAS6/Axl 阻断将减少慢性主动脉重塑时的肾脏和血管炎症，并减轻肾功能障碍。我们在小鼠中表征了一种在血管紧张素 II（ANG II）输注 2 周后的主动脉重塑模型。这些小鼠的脉搏波速度持续增加，其主动脉壁显示出增加的壁胶原。力学测试显示，ANG II 输注后 6 个月，Windkessel 功能明显丧失。肾功能研究显示，其排泄容量负荷的能力降低，白蛋白尿逐渐增加，过碘酸希夫染色估计肾小管损伤。ANG II 输注 2 个月后开始用 Axl 抑制剂 R428 治疗对 2 个月后的主动脉重塑作用不大，但可减少 T 细胞、γ/δ T 细胞和巨噬细胞浸润到主动脉和肾脏，并改善肾脏排泄能力，减少白蛋白尿，并减少肾小管损伤的证据。在人类中，循环 Axl/Siglec6 树突状细胞和磷酸化 Axl 细胞与经食管超声心动图测量的脉搏波速度和主动脉顺应性相关，证实了 GAS6/Axl 通路的慢性激活。我们的结论是，短暂的高血压发作会导致慢性主动脉重塑，这与主动脉和肾脏的持续低度炎症以及肾功能障碍的证据有关。这些事件至少部分通过 GAS6/Axl 信号转导介导，并且 Axl 阻断可改善这些事件。在这项研究中，小鼠短暂的 2 周高血压导致进行性主动脉重塑、脉搏波速度增加和肾脏损伤、功能障碍和白蛋白尿的证据。这种终末器官损伤与 CD8 和 γ/δ T 细胞持续浸润肾脏和主动脉有关。我们表明，这种炎症反应可能是由于 GAS6/Axl 信号，并且可以通过阻断该途径来改善。我们提出，由于脉搏波速度增加而导致的微血管力学力的改变增强了 GAS6 从内皮细胞的释放，这反过来又激活了骨髓细胞上的 Axl，促进了与主动脉僵硬相关的终末器官损伤。
