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
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DOI：
10.1152/ajpheart.00253.2022
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发表时间：
2022-11-01
影响因子：
4.8
通讯作者：
Harrison, David G.
中科院分区：
文献类型：
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作者：
Chen, Wei;Van Beusecum, Justin P.;Harrison, David G.
我们已经证明，过度的内皮细胞拉伸会导致生长停滞特异性 6 (GAS6) 的释放，从而激活单核细胞上的酪氨酸激酶受体 Axl 并促进免疫激活和炎症。我们假设 GAS6/Axl 阻断会减少肾脏和血管炎症，并减轻慢性主动脉重塑背景下的肾功能障碍。我们对小鼠输注血管紧张素 II (ANG II) 2 周后的主动脉重塑模型进行了表征。这些小鼠的脉搏波速度长期增加，并且它们的主动脉显示壁胶原蛋白增加。机械测试显示 Windkessel 功能明显丧失，并在 ANG II 输注后持续 6 个月。肾功能研究显示排泄容量负荷的能力降低、白蛋白尿逐渐增加以及通过高碘酸希夫染色估计的肾小管损伤。 ANG II输注后2个月开始使用Axl抑制剂R428治疗对2个月后的主动脉重塑影响很小，但减少了T细胞、c/6 T细胞和巨噬细胞向主动脉和肾脏的浸润，改善了肾脏排泄能力，减少了蛋白尿，并减少了肾小管损伤的证据。在人类中，循环 Axl+/Siglec6+ 树突状细胞和磷酸化 Axl+ 细胞与经食管回波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，短暂的高血压会诱发慢性主动脉重塑，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。这些事件至少部分是由 GAS6/Axl 信号传导介导的，并通过 Axl 阻断得到改善。新的和值得注意的在这项研究中，小鼠短暂的 2 周高血压导致进行性主动脉重塑、脉搏波速度增加以及肾损伤、功能障碍和蛋白尿的证据。这种终末器官损伤与 CD8+ 和 c/6 T 细胞持续肾脏和主动脉浸润有关。我们发现这种炎症反应可能是由 GAS6/Axl 信号传导引起的，并且可以通过阻断该途径来改善。我们认为，脉搏波速度增加引起的微血管机械力的改变增强了内皮细胞中 GAS6 的释放，进而激活骨髓细胞上的 Axl，促进与主动脉硬化相关的终末器官损伤。
We have shown that excessive endothelial cell stretch causes release of growth arrest-specific 6 (GAS6), which activates the ty-rosine 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, c/6 T cells, and macrophages into the aorta and kidney and improved renal excre-tory capacity, reduced albuminuria, and reduced evidence of renal tubular damage. In humans, circulating Axl+/Siglec6+ dendri-tic 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 dysfunc-tion. These events are mediated at least in part by GAS6/Axl signaling and are improved with Axl blockade.NEW & NOTEWORTHY 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 associ-ated with persistent renal and aortic infiltration of CD8+ and c/6 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 my-eloid cells, promoting the end-organ damage associated with aortic stiffening.