Conditional hypoxia inducible factor-1α induction in embryonic pulmonary epithelium impairs maturation and augments lymphangiogenesis.
Conditional hypoxia inducible factor-1α induction in embryonic pulmonary epithelium impairs maturation and augments lymphangiogenesis.
复制标题
DOI：
10.1016/j.ydbio.2011.10.033
复制
发表时间：
2012-02-01
影响因子：
2.7
通讯作者：
Shannon JM
中科院分区：
文献类型：
--
作者：
Bridges JP;Lin S;Ikegami M;Shannon JM
缺氧诱导因子（HIF） 1a、EPAS1和NEPAS在胚胎小鼠肺中表达，每种亚型在形态发生过程中表现出不同的时空表达模式。为了进一步评估HIF1a亚型在肺上皮细胞分化和稳态中的作用，我们创建了转基因小鼠，以多西环素依赖的方式表达人类HIF-1a的组成型活性亚型（HIF-1a三点突变体（TPM））。HIF1a TPM在发育中的肺上皮中的表达导致肺发育不全，其特征是分支形态发生缺陷、细胞能量改变和上皮成熟受损，最终导致新生儿因严重呼吸窘迫而死亡。组织学和生化分析显示，肺上皮细胞中糖原池在E18.5时扩大，同时肺表面活性物质减少，表明成熟延迟或停止。重要的是，这些缺陷发生在没有细胞凋亡或坏死的情况下。此外，HIF1a型TPM患者的肺早在E14.5时就出现了明显的胸膜下出血，尽管血管模式正常，这与内皮屏障功能缺陷一致。HIF1a TPM的上皮表达也导致内皮前体细胞中VEGFA和VEGFC的产生增加，淋巴管数量增加，间接激活多种Notch通路成分。综上所述，这些数据表明肺上皮中的HIF-1a蛋白水平必须受到严格控制，才能保证上皮和间质室的正常发育。
Hypoxia inducible factor (HIF) 1a, EPAS1 and NEPAS are expressed in the embryonic mouse lung and each isoform exhibits distinct spatiotemporal expression patterns throughout morphogenesis. To further assess the role of the HIF1a isoform in lung epithelial cell differentiation and homeostasis, we created transgenic mice that express a constitutively active isoform of human HIF-1a (HIF-1a three point mutant (TPM)), in a doxycycline-dependent manner. Expression of HIF1a TPM in the developing pulmonary epithelium resulted in lung hypoplasia characterized by defective branching morphogenesis, altered cellular energetics and impaired epithelial maturation, culminating in neonatal lethality at birth from severe respiratory distress. Histological and biochemical analyses revealed expanded glycogen pools in the pulmonary epithelial cells at E18.5, concomitant with decreased pulmonary surfactant, suggesting a delay or an arrest in maturation. Importantly, these defects occurred in the absence of apoptosis or necrosis. In addition, sub-pleural hemorrhaging was evident as early as E14.5 in HIF1a TPM lungs, despite normal patterning of the blood vasculature, consistent with defects in endothelial barrier function. Epithelial expression of HIF1a TPM also resulted in increased VEGFA and VEGFC production, an increase in the number of lymphatic vessels and indirect activation of the multiple Notch pathway components in endothelial precursor cells. Collectively, these data indicate that HIF-1a protein levels in the pulmonary epithelium must be tightly controlled for proper development of the epithelial and mesenchymal compartments.
登录
查看更多内容
影响因子：
11.4
作者：
Ema, M;Hirota, K;Fujii-Kuriyama, Y
通讯作者：
Fujii-Kuriyama, Y
影响因子：
19.6
作者：
Gassmann, M;Kvietikova, I;Wenger, RH
通讯作者：
Wenger, RH
影响因子：
6.5
作者：
Fitzgerald, Michael L.;Xavier, Ramnik;Freeman, Mason W.
通讯作者：
Freeman, Mason W.
影响因子：
4.4
作者：
Dioum, Elhadji M.;Clarke, Stephen L.;Garcia, Joseph A.
通讯作者：
Garcia, Joseph A.
影响因子：
5.3
作者：
Goda, N;Ryan, HE;Johnson, RS
通讯作者：
Johnson, RS