Spinetti Gaia, Wang Mingyi, Monticone Robert, Zhang Jing, Zhao Di, Lakatta Edward G
Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr, Baltimore, MD 21224, USA.
Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1397-402. doi: 10.1161/01.ATV.0000134529.65173.08. Epub 2004 Jun 3.
With age, rat arterial walls thicken and vascular smooth muscle cells (VSMCs) exhibit enhanced migration and proliferation. Monocyte chemotactic protein-1 (MCP-1) affects these VSMC properties in vitro. Because arterial angiotensin II, which induces MCP-1 expression, increases with age, we hypothesized that aortic MCP-1 and its receptor CCR2 are also upregulated and affect VSMC properties.
Both MCP-1 and CCR2 mRNAs and proteins increased in old (30-month) versus young (8-month) F344xBN rat aortas in vivo. Cellular MCP-1 and CCR2 staining colocalized with that of alpha-smooth muscle actin in the thickened aortas of old rats and were expressed by early-passage VSMCs isolated from old aortas, which, relative to young VSMCs, exhibited increased invasion, and the age difference was abolished by vCCI, an inhibitor of CCR2 signaling. MCP-1 treatment of young VSMCs induced migration and increased their ability to invade a synthetic basement membrane. The MCP-1-dependent VSMC invasiveness was blocked by vCCI. After MCP-1 treatment, migration and invasion capacities of VSMCs from young aortas no longer differed from those of VSMCs isolated from older rats.
Arterial wall and VSMC MCP-1/CCR2 increase with aging. MCP-1 enhances VSMC migration and invasion, and thus, MCP-1/CCR2 signaling may play a role in age-associated arterial remodeling.
随着年龄增长,大鼠动脉壁增厚,血管平滑肌细胞(VSMC)迁移和增殖增强。单核细胞趋化蛋白-1(MCP-1)在体外影响这些VSMC特性。由于诱导MCP-1表达的动脉血管紧张素II随年龄增加,我们推测主动脉MCP-1及其受体CCR2也上调并影响VSMC特性。
在体内,老年(30个月)F344xBN大鼠主动脉中MCP-1和CCR2的mRNA及蛋白水平均高于年轻(8个月)大鼠。在老年大鼠增厚的主动脉中,细胞MCP-1和CCR2染色与α-平滑肌肌动蛋白染色共定位,且从老年主动脉分离的早期传代VSMC表达MCP-1和CCR2。相对于年轻VSMC,老年VSMC的侵袭能力增强,而CCR2信号抑制剂vCCI可消除这种年龄差异。用MCP-1处理年轻VSMC可诱导其迁移并增强其侵袭合成基底膜的能力。vCCI可阻断MCP-1依赖的VSMC侵袭性。MCP-1处理后,年轻主动脉VSMC的迁移和侵袭能力与老年大鼠分离的VSMC不再有差异。
动脉壁和VSMC的MCP-1/CCR2随衰老而增加。MCP-1增强VSMC迁移和侵袭,因此,MCP-1/CCR2信号可能在与年龄相关的动脉重塑中起作用。