Notch2 and Notch3 function together to regulate vascular smooth muscle development.
Notch2 and Notch3 function together to regulate vascular smooth muscle development.
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DOI：
10.1371/journal.pone.0037365
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lilly B
中科院分区：
文献类型：
--
作者：
Wang Q;Zhao N;Kennard S;Lilly B
Notch信号转导与平滑肌分化的调节有关，但Notch受体的确切作用尚不清楚。尽管Notch3受体在平滑肌中表达高，但Notch3突变小鼠是可行的，并且在血管图案化和平滑肌分化中仅显示轻度缺陷。Notch2也在平滑肌中表达，并且Notch2突变小鼠显示出指示平滑肌缺陷的心血管异常。总之，这些发现推断Notch2和Notch3共同作用以控制血管发育和平滑肌分化。为了解决这一假设，我们表征了Notch2和Notch3联合缺陷小鼠的表型。我们的研究结果表明，当Notch2和Notch3基因同时被破坏时，小鼠在妊娠中期由于严重的血管异常而在子宫内死亡。通过Pecam 1表达评估，血管网络的组装正常发生，然而血管周围的平滑肌细胞严重缺乏，导致血管塌陷。体外分析表明，Notch2和Notch3都能强烈激活平滑肌分化基因，Notch3是Notch信号传导的靶标，而Notch2不是。这些数据突出了Notch受体在调节血管发育中的联合作用，并表明虽然这些受体在平滑肌中表现出代偿作用，但它们的功能并不完全重叠。
Notch signaling has been implicated in the regulation of smooth muscle differentiation, but the precise role of Notch receptors is ill defined. Although Notch3 receptor expression is high in smooth muscle, Notch3 mutant mice are viable and display only mild defects in vascular patterning and smooth muscle differentiation. Notch2 is also expressed in smooth muscle and Notch2 mutant mice show cardiovascular abnormalities indicative of smooth muscle defects. Together, these findings infer that Notch2 and Notch3 act together to govern vascular development and smooth muscle differentiation. To address this hypothesis, we characterized the phenotype of mice with a combined deficiency in Notch2 and Notch3. Our results show that when Notch2 and Notch3 genes are simultaneously disrupted, mice die in utero at mid-gestation due to severe vascular abnormalities. Assembly of the vascular network occurs normally as assessed by Pecam1 expression, however smooth muscle cells surrounding the vessels are grossly deficient leading to vascular collapse. In vitro analysis show that both Notch2 and Notch3 robustly activate smooth muscle differentiation genes, and Notch3, but not Notch2 is a target of Notch signaling. These data highlight the combined actions of the Notch receptors in the regulation of vascular development, and suggest that while these receptors exhibit compensatory roles in smooth muscle, their functions are not entirely overlapping.
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DOI：
10.1073/pnas.0709663105
发表时间：
2008-02-12
影响因子：
11.1
作者：
High, Frances A.;Lu, Min Min;Epstein, Jonathan A.
通讯作者：
Epstein, Jonathan A.
影响因子：
2.5
作者：
Varadkar, Prajakta;Kraman, Matthew;McCright, Brent
通讯作者：
McCright, Brent
影响因子：
--
作者：
Gridley, Thomas
通讯作者：
Gridley, Thomas
影响因子：
20.1
作者：
Liu H;Zhang W;Kennard S;Caldwell RB;Lilly B
通讯作者：
Lilly B
影响因子：
10.5
作者：
Domenga, V;Fardoux, P;Joutel, A
通讯作者：
Joutel, A