Central Arterial Aging: Humans to Molecules

在人的一生中，中央动脉的结构和功能会发生变化。了解动脉壁如何老化是至关重要的，不仅因为它对动脉和心脏的结构和功能有深远的影响，而且还因为随着年龄的增长而重塑的中央动脉为动脉疾病奠定了基础。众所周知，弥漫性内膜增厚是伴随年龄增长的中心动脉的标志，但其分子机制尚不清楚。我们小组进行了一系列关于啮齿动物、非人类灵长类动物和人类动脉老化的研究。在Fisher 344杂交褐挪威大鼠（FXBN）中，血管紧张素II （Ang II）蛋白、基质金属蛋白酶-2活化（MMP-2）和转化生长因子- b1 （TGF-B1）的显著增加与年龄相关。在增厚的动脉内膜内观察到，包括浸润的血管平滑肌细胞（VSMCs）和沉积的胶原和纤维连接蛋白（FN）。有趣的是，在年龄较大的雄性猴子中，在含有大量VSMC和胶原的增厚的主动脉内膜中检测到Ang II和MMP-2的上调。值得注意的是，我们还发现，在远离动脉粥样硬化斑块的人类增厚动脉内膜中，Ang II和MMP活性都上调。因此，Ang II和MMP-2伴随年龄相关的动脉重塑。为了分析这种关系，我们将Ang II注入幼鼠体内。年轻大鼠给予Ang II可增加动脉MMP-2和TGF-B1活性，VSMCs内膜浸润和胶原沉积。这几乎再现了上述在老年大鼠中观察到的年轻大鼠动脉壁的所有结构和分子特征。此外，TGF-B1激活至少部分依赖于伴随年龄相关的MMP-2活性增加；单核细胞趋化蛋白-1 (MCP-1)，一种Ang信号的下游分子，在老龄大鼠主动脉壁内显著增加。

The structure and function of central arteries change throughout the lifetime of humans. An understanding of how the arterial wall ages is crucial not only because of its profound effects on arterial and cardiac structure and function, but also because the central artery, remodeled by aging, sets the stage for arterial diseases. It is well known that the diffuse intima thickening is a hallmark of the central arteries that accompanies advancing age, but the molecular mechanisms remain poorly understood. A series of studies on arterial aging in rodents, nonhuman primates, and humans have been performed in our group. In Fisher 344 corssbred Brown Norway rats (FXBN), the marked age-associated increases in the angiotensin II (Ang II) protein, martix metalloproteinase-2 activation (MMP-2), and transforming growth factor-B1 (TGF-B1). Are observed within the thickened arterial intima, including infiltrated vascular smooth muscle cells (VSMCs) and deposited collagen and fibronectin (FN). Interestingly, in older male monkeys, an upregulation of both Ang II and MMP-2 is detected in the thickened aortic intimae, contining numerous VSMC and collagen. Notably, we also found that both Ang II and MMP activity are upregulated in the thickened arterial intima of humans in areas remote from atherosclerotic plaques with aging. Thus, Ang II and MMP-2 accompany age-associated arterial remodeling. To analyze this relationship, we infused Ang II into young rats. An administration of Ang II to young rats increases arterial MMP-2 and TGF-B1 activity, intima infiltration by VSMCs, and collagen deposition. This reproduces nearly all of the aforementioned structural and molecular features of the arterial wall in young rats that have been observed in older rats. Furthermore, TGF-B1 activation is dependent, in part at least, by a concomitant age-associated increase in MMP-2 activity; and monocyte chemoattractant protein-1 (MCP-1), a downstream molecule of Ang signaling, is markedly increased within the older aortic wall in rats. These findings point at a central role for Ang II and associated signaling molecules in arterial aging. MMP-2, MCP-1, TGF-B1, collagen and FN production are all downstream events of Ang II-AT1 receptor signaling. The age-associated increases of these related molecules within the older remodeled aorta implicate local arterial Ang II signaling pathways as targets for prevention or amelioration of arterial remodeling, and its attendant risk for the incidence and severity of arterial diseases that increase exponentially with advancing age.