LRP1 functions as an atheroprotective integrator of TGFbeta and PDFG signals in the vascular wall: implications for Marfan syndrome.
LRP1 functions as an atheroprotective integrator of TGFbeta and PDFG signals in the vascular wall: implications for Marfan syndrome.
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DOI：
10.1371/journal.pone.0000448
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发表时间：
2007-05-16
期刊：
影响因子：
3.7
通讯作者：
Herz, Joachim
中科院分区：
文献类型：
--
作者：
Boucher, Philippe;Li, Wei-Ping;Matz, Rachel L.;Takayama, Yoshiharu;Auwerx, Johan;Anderson, Richard G. W.;Herz, Joachim
多功能受体LRP1调控血管平滑肌细胞中血小板衍生生长因子受体β的表达、活性和转运。LRP1也是转化生长因子β-1的受体，在转化生长因子β介导的细胞增殖抑制中是必需的。我们发现，在体内缺失LRP1的血管平滑肌细胞(SmLRP−)会导致马凡样综合征，伴随着磷酸化Smad2/3的核聚集，弹力层断裂，主动脉扭曲，转化生长因子β靶基因血栓反应蛋白-1(TSP1)和PDGFFRβ在血管壁的表达增加。用PPAR−激动剂罗格列酮治疗SmLRP1γ动物可消除核内pSmad积聚，逆转马凡样表型，并显著减少血管平滑肌增殖、纤维化和动脉粥样硬化，而不依赖于血浆胆固醇水平。我们的发现与LRP1缺陷的血管壁中转化生长因子β信号的激活是一致的。LRP1可能作为增殖和抗增殖信号的整合因子，控制马凡综合征和动脉粥样硬化发病的共同生理机制，这对于维持血管壁的完整性是必不可少的。
The multifunctional receptor LRP1 controls expression, activity and trafficking of the PDGF receptor-β in vascular smooth muscle cells (VSMC). LRP1 is also a receptor for TGFβ1 and is required for TGFβ mediated inhibition of cell proliferation. We show that loss of LRP1 in VSMC (smLRP−) in vivo results in a Marfan-like syndrome with nuclear accumulation of phosphorylated Smad2/3, disruption of elastic layers, tortuous aorta, and increased expression of the TGFβ target genes thrombospondin-1 (TSP1) and PDGFRβ in the vascular wall. Treatment of smLRP1− animals with the PPARγ agonist rosiglitazone abolished nuclear pSmad accumulation, reversed the Marfan-like phenotype, and markedly reduced smooth muscle proliferation, fibrosis and atherosclerosis independent of plasma cholesterol levels. Our findings are consistent with an activation of TGFβ signals in the LRP1-deficient vascular wall. LRP1 may function as an integrator of proliferative and anti-proliferative signals that control physiological mechanisms common to the pathogenesis of Marfan syndrome and atherosclerosis, and this is essential for maintaining vascular wall integrity.
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