Complement-Mediated Macrophage Polarization in Perivascular Adipose Tissue Contributes to Vascular Injury in Deoxycorticosterone Acetate-Salt Mice
Complement-Mediated Macrophage Polarization in Perivascular Adipose Tissue Contributes to Vascular Injury in Deoxycorticosterone Acetate-Salt Mice
复制标题
血管周围脂肪组织中补体介导的巨噬细胞极化导致脱氧皮质酮醋酸盐小鼠的血管损伤
DOI：
10.1161/atvbaha.114.304927
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发表时间：
2015
影响因子：
8.7
通讯作者：
Gao Ping-Jin
中科院分区：
文献类型：
--
作者：
Ruan Cheng-Chao;Ge Qian;Li Yan;Li Xiao-Dong;Chen Dong-Rui;Ji Kai-Da;Wu Yong-Jie;Sheng Li-Juan;Yan Chen;Zhu Ding-Liang;Gao Ping-Jin
目的在脱氧皮质酮-盐性高血压模型中，血管周围脂肪组织(PVAT)中补体3(C3)的表达增加。本研究旨在探讨C3在PVAT中的作用及其机制，以进一步了解高血压血管重构的发病机制。方法与结果利用野生型和C3缺陷型(C3KO)小鼠的腹膜巨噬细胞，研究了C3在巨噬细胞极化中的作用，因为我们发现C3主要表达于DOCA-SALT小鼠的PVAT中的巨噬细胞，结果显示C3KO巨噬细胞中M1表型标记的表达减少，而M2标记的表达增加。体内骨髓移植研究进一步表明，供体为C3KO的供体骨髓与野生型小鼠相比，DOCA-SALT受体小鼠PVAT中M1巨噬细胞减少，M2巨噬细胞增多。值得注意的是，这种巨噬细胞极化转变伴随着血管损伤的改善。此外，我们确定补体5a(C5a)是参与巨噬细胞极化和DOCA盐诱导的血管损伤的主要C3激活产物。结论在PVAT中，骨髓来源的巨噬细胞的存在和激活对补体活化在高血压血管炎症中起关键作用，而C5a通过刺激巨噬细胞向促炎性M1表型分化而在DOCA盐诱导的血管损伤中起关键作用。
ObjectiveWe have previously shown an increased expression of complement 3 (C3) in the perivascular adipose tissue (PVAT) in the deoxycorticosterone acetate (DOCA)–salt hypertensive model. This study aims to examine the role and underlying mechanism of C3 in PVAT for understanding the pathogenesis of hypertensive vascular remodeling further.Approach and ResultsThe role of C3 in macrophage polarization was investigated using peritoneal macrophages from wild-type and C3-deficient (C3KO) mice because we found that C3 was primarily expressed in macrophages in PVAT of blood vessels from DOCA-salt mice, and results showed a decreased expression of M1 phenotypic marker in contrast to an increased level of M2 marker in the C3KO macrophages. Bone marrow transplantation studies further showed in vivo that DOCA-salt recipient mice had fewer M1 but more M2 macrophages in PVAT when the donor bone marrows were from C3KO compared with those from wild-type mice. Of note, this macrophage polarization shift was accompanied with an ameliorated vascular injury. Furthermore, we identified the complement 5a (C5a) as the major C3 activation product that was involved in macrophage polarization and DOCA-salt–induced vascular injury. Consistently, in vivo depletion of macrophages prevented the induction of C3 and C5a in PVAT, and ameliorated hypertensive vascular injury as well.ConclusionsThe presence and activation of bone marrow–derived macrophages in PVAT are crucial for complement activation in hypertensive vascular inflammation, and C5a plays a critical role in DOCA-salt–induced vascular injury by stimulating macrophage polarization toward a proinflammatory M1 phenotype in PVAT.