Axl, a receptor tyrosine kinase, mediates flow-induced vascular remodeling
Axl, a receptor tyrosine kinase, mediates flow-induced vascular remodeling
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DOI：
10.1161/01.res.0000223322.16149.9a
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发表时间：
2006-06-09
影响因子：
20.1
通讯作者：
Berk, BC
中科院分区：
文献类型：
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作者：
Korshunov, VA;Mohan, AM;Berk, BC
血流动力学应激引起的内中膜增厚(IMT)是一个生理过程，需要内皮细胞、炎症细胞和血管平滑肌细胞(VSMC)之间的协调信号。AX1是一种受体酪氨酸激酶，其配体为Gas6，在颈动脉损伤后VSMC中高度诱导表达。由于Axl调节细胞迁移、吞噬和细胞凋亡，我们推测Axl可能在IMT中发挥作用。通过结扎维持左枕动脉血流的左颈动脉(LCA)分支，诱导AXL缺陷小鼠(AXL(-/-))和野生型小鼠(AXL(-/-))的血管重构。两种基因型的基线血流动力学参数和颈动脉结构相似。部分结扎对两种基因型的血流量影响相同：右颈动脉(RCA)增加60%，而LCA减少80%。RCA重构在不同基因型间差异无统计学意义。然而，在LCA中，AXL(-/-)比AXL(-/-)形成的内膜+中层明显更小(分别为31+/-4比42+/-6×10(-6)µm(3))。免疫组织化学定量显示Axl(-/-)LCA的细胞凋亡率高于Axl(-/-)(5倍)。正如预期的那样，p-Akt在Ax1(-/-)中降低，而在Gas6的表达没有差异。细胞组成也发生了显著变化，与AXL(-/-)相比，AXL(-/-)的CD45(+)细胞增多，VSMC、巨噬细胞和中性粒细胞减少。这些数据表明Axl通过调节血管细胞凋亡和血管炎症在血流依赖性重塑中发挥重要作用。
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 +/- 6x10(-6) mu m(3), 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.