Kondo Yuka, Jadlowiec Caroline C, Muto Akihito, Yi Tai, Protack Clinton, Collins Michael J, Tellides George, Sessa William C, Dardik Alan
The Vascular Biology and Therapeutics Program and the Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, United States of America ; Mie University Graduate School of Medicine, Department of Thoracic and Cardiovascular Surgery, Tsu, Japan.
PLoS One. 2013 Nov 20;8(11):e81019. doi: 10.1371/journal.pone.0081019. eCollection 2013.
Nogo-B mediates vascular protection and facilitates monocyte- and macrophage-dependent vascular remodeling. PirB is an alternate receptor for Nogo-B, but a role for the Nogo-PirB axis within the vascular system has not been previously reported. We examined whether Nogo-B or PirB play a role in regulating macrophage-mediated vascular remodeling and hypothesized that endothelial Nogo-B regulates vein graft macrophage infiltration via its alternate receptor PirB.
Vein grafts were performed using Nogo and PirB wild type and knockout mice. Human vein grafts were similarly analyzed. The hindlimb ischemia model was performed in PirB wild type and knockout mice. Accompanying in vitro work included isolation of macrophages from PirB wild type and knockout mice.
Increased Nogo-B and PirB mRNA transcripts and protein expression were observed within mouse and human vein grafts. Both Nogo knockout and PirB knockout vein grafts showed increased wall thickness and increased numbers of F4/80-positive macrophages. Macrophages derived from PirB knockout mice had increased adhesion to fibronectin, increased EC-specific binding, and increased numbers of mRNA transcripts of M2 markers as well as MMP3 and MMP9. PirB knockout vein grafts had increased active MMP9 compared to wild type vein grafts. PirB knockout mice had increased recovery from hindlimb ischemia and increased macrophage infiltration compared to wild type mice.
Vein graft adaptation shows increased expression of both Nogo-B and PirB. Loss of PirB, or its endothelial ligand Nogo-B, results in increased inflammatory cell infiltration and vein graft wall thickening. These findings suggest that PirB regulates macrophage activity in vein grafts and that Nogo-B in the vein graft limits macrophage infiltration and vein graft thickening. PirB may play a more general role in regulating macrophage responses to vascular injury. Macrophage inhibition via Nogo-PirB interactions may be an important mechanism regulating vein graft adaptation to the arterial circulation.
Nogo-B介导血管保护并促进单核细胞和巨噬细胞依赖性血管重塑。PirB是Nogo-B的一种替代受体，但Nogo-PirB轴在血管系统中的作用此前尚未见报道。我们研究了Nogo-B或PirB是否在调节巨噬细胞介导的血管重塑中发挥作用，并假设内皮细胞Nogo-B通过其替代受体PirB调节静脉移植物巨噬细胞浸润。
使用Nogo和PirB野生型及基因敲除小鼠进行静脉移植。对人静脉移植物进行类似分析。在PirB野生型和基因敲除小鼠中建立后肢缺血模型。相关的体外研究包括从PirB野生型和基因敲除小鼠中分离巨噬细胞。
在小鼠和人静脉移植物中观察到Nogo-B和PirB mRNA转录本及蛋白表达增加。Nogo基因敲除和PirB基因敲除的静脉移植物均显示壁厚增加以及F4/80阳性巨噬细胞数量增加。源自PirB基因敲除小鼠的巨噬细胞对纤连蛋白的黏附增加、对内皮细胞特异性结合增加，且M2标志物以及MMP3和MMP9的mRNA转录本数量增加。与野生型静脉移植物相比，PirB基因敲除的静脉移植物中活性MMP9增加。与野生型小鼠相比，PirB基因敲除小鼠后肢缺血恢复增加且巨噬细胞浸润增加。
静脉移植物适应性表现为Nogo-B和PirB表达均增加。PirB或其内皮配体Nogo-B的缺失导致炎症细胞浸润增加和静脉移植物壁增厚。这些发现表明PirB调节静脉移植物中的巨噬细胞活性，且静脉移植物中的Nogo-B限制巨噬细胞浸润和静脉移植物增厚。PirB可能在调节巨噬细胞对血管损伤的反应中发挥更广泛的作用。通过Nogo-PirB相互作用抑制巨噬细胞可能是调节静脉移植物适应动脉循环的重要机制。
