Endothelial outgrowth cells shift macrophage phenotype and improve kidney viability in swine renal artery stenosis.
Endothelial outgrowth cells shift macrophage phenotype and improve kidney viability in swine renal artery stenosis.
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DOI：
10.1161/atvbaha.113.301164
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发表时间：
2013-05
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影响因子：
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通讯作者：
Lerman LO
中科院分区：
文献类型：
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作者：
Eirin A;Zhu XY;Li Z;Ebrahimi B;Zhang X;Tang H;Korsmo MJ;Chade AR;Grande JP;Ward CJ;Simari RD;Lerman A;Textor SC;Lerman LO
内皮生长细胞（EOC）减少炎症和改善内皮修复。炎症加重了肾动脉狭窄（RAS）的肾损伤，并可能解释其在血运重建后的持续性。我们假设EOC可以减少炎症（M1）巨噬细胞，改善RAS的肾脏恢复。在经皮腔内肾血管成形术（PTRA+支架植入术）或假手术后4周，研究了患有10周RAS的猪，伴或不伴辅助肾内输送自体EOC（10×10^6），并与相似治疗的正常对照组（每组n=7）进行比较。评价单肾功能、微血管和组织重塑、炎症、氧化应激和纤维化。PTRA后4周，EOC植入注射的RAS-肾。RAS+EOC、RAS+PTRA和RAS+PTRA+EOC猪的肾小球滤过率得到恢复，而仅EOC处理猪的肾小球滤过率和血管生成得到改善，纤维化减弱。此外，EOC增加了细胞增殖，降低了M1（炎症）/M2（修复）巨噬细胞的比例，以及炎症细胞因子的循环水平和肾脏释放。培养的EOC在体外释放微泡，并诱导培养的单核细胞中的表型转换（M1至M2），这被VEGF阻断抑制。最后，在另外7只RAS猪中单次肾内注射rhVEGF（0.05 μg/kg）也在4周后恢复了M1/M2比率。PTRA后肾内输注EOC诱导VEGF介导的巨噬细胞炎症表型衰减，保留微血管结构和功能，并减少狭窄肾脏中的炎症和纤维化，这表明在实验RAS中连续给予EOC以改善PTRA结局的新机制和治疗潜力。
Endothelial outgrowth cells (EOC) decrease inflammation and improve endothelial repair. Inflammation aggravates kidney injury in renal artery stenosis (RAS), and may account for its persistence upon revascularization. We hypothesized that EOC would decrease inflammatory (M1) macrophages and improve renal recovery in RAS. Pigs with 10 weeks of RAS were studied 4 weeks after percutaneous transluminal renal angioplasty (PTRA+stenting) or sham, with or without adjunct intra-renal delivery of autologous EOC (10×10^6), and compared to similarly-treated normal controls (n=7 each). Single-kidney function, microvascular and tissue remodeling, inflammation, oxidative stress, and fibrosis were evaluated. Four weeks after PTRA, EOC engrafted in injected RAS-kidneys. Stenotic-kidney glomerular filtration rate was restored in RAS+EOC, RAS+PTRA, and RAS+PTRA+EOC pigs, while stenotic-kidney blood flow and angiogenesis were improved and fibrosis attenuated only in EOC-treated pigs. Furthermore, EOC increased cell proliferation and decreased the ratio of M1 (inflammatory)/M2 (reparative) macrophages, as well as circulating levels and stenotic-kidney release of inflammatory cytokines. Cultured-EOC released microvesicles in-vitro and induced phenotypic switch (M1-to-M2) in cultured monocytes, which was inhibited by VEGF blockade. Finally, a single intra-renal injection of rhVEGF (0.05 μg/kg) in 7 additional RAS pigs also restored M1/M2 ratio 4 weeks later. Intra-renal infusion of EOC after PTRA induced a VEGF-mediated attenuation in macrophages inflammatory phenotype, preserved microvascular architecture and function, and decreased inflammation and fibrosis in the stenotic kidney, suggesting a novel mechanism and therapeutic potential for adjunctive EOC delivery in experimental RAS to improve PTRA outcomes.