Targeted disruption of TGF-β-Smad3 signaling leads to enhanced neointimal hyperplasia with diminished matrix deposition in response to vascular injury
Targeted disruption of TGF-β-Smad3 signaling leads to enhanced neointimal hyperplasia with diminished matrix deposition in response to vascular injury
复制标题
DOI：
10.1161/01.res.0000163980.55495.44
复制
发表时间：
2005-04-29
影响因子：
20.1
通讯作者：
Saito, Y
中科院分区：
文献类型：
--
作者：
Kobayashi, K;Yokote, K;Saito, Y
转化生长因子（TGF）-β及其信号在动脉粥样硬化形成中的作用尚未完全了解。在这里，我们研究了缺乏Smad 3（TGF-β的主要下游介质）的小鼠，以阐明Smad 3依赖性信号传导在血管损伤反应中的确切作用。在C57 Bl/6背景下，在野生型和Smad 3-null（null）雄性小鼠中损伤股动脉。损伤后1 - 3周的动脉组织学评价显示，与野生型小鼠相比，null小鼠的新生内膜增生显著增强。将空骨髓移植到野生型小鼠体内并没有增强新生内膜增厚，这表明原位血管细胞在反应中发挥着重要作用。与野生型内膜相比，血管内膜含有更多的增殖平滑肌细胞（SMC），胶原含量较少。TGF-β在野生型主动脉SMC中引起细胞增殖的显著抑制，而在体外，TGF-β仅微弱地抑制无效SMC的生长，表明Smad 3在生长抑制功能中的关键作用。另一方面，Smad 3缺陷并没有减弱SMC对TGF-β的趋化性。TGF-β增加α 2型I型胶原和金属蛋白酶组织抑制剂1的转录水平，抑制基质金属蛋白酶的表达和活性。然而，TGF-β的这些作用在无效SMC中减弱。我们的研究结果表明，Smad 3通路的丢失通过调节血管SMC的生长和基质调节而导致损伤后新生内膜增生增强。这些结果表明内源性Smad 3在响应损伤中的血管保护作用。
The role of transforming growth factor (TGF)-beta and its signal in atherogenesis is not fully understood. Here, we examined mice lacking Smad3, a major downstream mediator of TGF-beta, to clarify the precise role of Smad3-dependent signaling in vascular response to injury. Femoral arteries were injured in wild-type and Smad3-null ( null) male mice on C57Bl/6 background. Histopathological evaluation of the arteries 1 to 3 weeks after the injury revealed significant enhancement of neointimal hyperplasia in null compared with wild-type mice. Transplantation of null bone marrow to wild-type mice did not enhance neointimal thickening, suggesting that vascular cells in situ play a major role in the response. Null intima contained more proliferating smooth muscle cells (SMC) with less amount of collagen compared with wild-type intima. TGF-beta caused significant inhibition of cellular proliferation in wild-type aortic SMC, whereas the growth of null SMC was only weakly inhibited by TGF-beta in vitro, indicating a crucial role of Smad3 in the growth inhibitory function. On the other hand, Smad3-deficiency did not attenuate chemotaxis of SMC toward TGF-beta. TGF-beta increased transcript level of alpha 2 type I collagen and tissue inhibitor of metalloproteinases-1, and suppressed expression and activity of matrix metalloproteinases in wild-type SMC. However, these effects of TGF-beta were diminished in null SMC. Our findings altogether show that the loss of Smad3 pathway causes enhanced neointimal hyperplasia on injury through modulation of growth and matrix regulation in vascular SMC. These results indicate a vasculoprotective role of endogenous Smad3 in response to injury.