Evaluation of Notch3 Deficiency in Diabetes-Induced Pericyte Loss in the Retina.
Evaluation of Notch3 Deficiency in Diabetes-Induced Pericyte Loss in the Retina.
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DOI：
10.1159/000493151
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发表时间：
2018
影响因子：
1.7
通讯作者：
Lilly B
中科院分区：
文献类型：
--
作者：
Liu H;Zhang W;Lilly B
长期以来，血管周细胞的丢失与糖尿病视网膜病变的发生有关，然而导致周细胞脱落的机制尚不清楚。Notch3与周细胞的稳定性和存活有关，并与血管完整性有关。Notch3突变小鼠表现出视网膜周细胞的进行性损失。鉴于糖尿病视网膜病变与周细胞损失有关，我们试图确定Notch3信号转导的扰动是否有助于糖尿病诱导的周细胞脱落和毛细血管变性。我们利用周细胞表达的LacZ转基因（XlacZ4）来检查I型糖尿病小鼠模型（Ins2秋田）和Notch3缺陷小鼠视网膜中的周细胞损失。Notch3缺失动物在8周龄时表现出LacZ标志物的显著损失，而Ins2秋田糖尿病和Notch3杂合小鼠表现出更慢和更细微的LacZ损失。虽然在Ins2秋田糖尿病动物中组合Notch3杂合性没有显示进一步的缺陷，但胰蛋白酶消化法显示Notch3单倍不足增加了糖尿病小鼠中无细胞毛细血管的形成。我们的数据进一步表明，Notch信号在糖尿病视网膜和暴露于高血糖的细胞中是钝化的。这些结果首次证明了Notch3信号传导、周细胞损失和糖尿病视网膜病变之间的关联。
Loss of vascular pericytes has long been associated with the onset of diabetic retinopathy, however mechanisms contributing to pericyte dropout are not understood. Notch3 has been implicated in pericyte stability and survival, and linked to vascular integrity. Notch3 mutant mice exhibit progressive loss of retinal pericytes. Given that diabetic retinopathy is associated with pericyte loss, we sought to determine if perturbation of Notch3 signaling contributes to diabetes-induced pericyte dropout and capillary degeneration. We utilized a pericyte-expressed LacZ transgene (XlacZ4) to examine pericyte loss in retinas of a type I diabetic mouse model (Ins2Akita) and Notch3 deficient mice. Notch3 null animals showed a dramatic loss of the LacZ marker by 8 weeks of age, while Ins2Akita diabetic and Notch3 heterozygous mice exhibited a much slower and subtler loss of LacZ. Although combined Notch3 heterozygosity in Ins2Akita diabetic animals did not show further deficits, trypsin digest method revealed that Notch3 haploinsufficiency increased the formation of acellular capillary in diabetic mice. Our data further indicate that Notch signaling is blunted in diabetic retinas and in cells exposed to hyperglycemia. These results are the first to demonstrate an association between Notch3 signaling, pericyte loss and diabetic retinopathy.
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影响因子：
1.2
作者：
Hofmann, Jennifer J.;Iruela-Arispe, M. Luisa
通讯作者：
Iruela-Arispe, M. Luisa
周细胞迁移：实验性糖尿病性视网膜病中周细胞丧失的一种新型机制。
影响因子：
7.7
作者：
Pfister, Frederick;Feng, Yuxi;Hagen, Franziska Vom;Gans, Rijk;Deutsch, Urban;Hammes, Hans-Peter
通讯作者：
Hammes, Hans-Peter
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：
4.6
作者：
Kofler NM;Cuervo H;Uh MK;Murtomäki A;Kitajewski J
通讯作者：
Kitajewski J