Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification.
Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification.
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DOI：
10.1161/circresaha.110.219071
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发表时间：
2010-08-20
影响因子：
20.1
通讯作者：
Boström KI
中科院分区：
文献类型：
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作者：
Yao Y;Bennett BJ;Wang X;Rosenfeld ME;Giachelli C;Lusis AJ;Boström KI
骨形态发生蛋白 (BMP) 是形态发生素家族，被认为是血管壁钙化和炎症的介质。目的 研究 BMP 抑制剂 Matrix Gla 蛋白 (MGP) 表达的改变对血管疾病的影响。我们使用 MGP 转基因或 MGP 缺陷小鼠与载脂蛋白 E 小鼠（动脉粥样硬化模型）繁殖。 MGP 过表达会降低血管 BMP 活性、动脉粥样硬化病变大小、内膜和内侧钙化以及炎症。它还减少了激活素样激酶受体 (ALK)1 和血管内皮生长因子 (VEGF) 的表达，VEGF 是 BMP 激活途径的一部分，可调节血管生成，并可能增强病变形成和钙化。相反，MGP 缺乏会增加 BMP 活性，这可能解释了 MGP 缺乏的主动脉中血管内侧细胞的弥漫性钙化，以及 ALK1 和 VEGF 表达的增加。出乎意料的是，MGP缺陷小鼠的动脉粥样硬化病变形成减少，这可能是由于限制单核细胞浸润动脉壁的内皮粘附分子表达急剧减少所致。我们的结果表明，BMP 信号传导是血管疾病的关键调节因子，需要仔细控制以维持正常的血管稳态。
The bone morphogenetic proteins (BMP), a family of morphogens, have been implicated as mediators of calcification and inflammation in the vascular wall. To investigate the effect of altered expression of Matrix Gla Protein (MGP), an inhibitor of BMP, on vascular disease. We used MGP transgenic or MGP deficient mice bred to apolipoprotein E mice, a model of atherosclerosis. MGP overexpression reduced vascular BMP activity, atherosclerotic lesion size, intimal and medial calcification, and inflammation. It also reduced expression of the activin-like kinase receptor (ALK)1 and the vascular endothelial growth factor (VEGF), part of a BMP-activated pathway that regulates angiogenesis and may enhance lesion formation and calcification. Conversely, MGP deficiency increased BMP activity, which may explain the diffuse calcification of vascular medial cells in MGP deficient aortas, and the increase in expression of ALK1 and VEGF. Unexpectedly, atherosclerotic lesion formation was decreased in MGP deficient mice, which may be explained by a dramatic reduction in expression of endothelial adhesion molecules limiting monocyte infiltration of the artery wall. Our results indicate that BMP signaling is a key regulator of vascular disease, requiring careful control to maintain normal vascular homeostasis.