Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier
Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier
复制标题
DOI：
10.1016/j.devcel.2015.05.008
复制
发表时间：
2015-07-06
影响因子：
11.8
通讯作者：
Carlsson, Peter
中科院分区：
文献类型：
--
作者：
Reyahi, Azadeh;Nik, Ali M.;Carlsson, Peter
周细胞对脑血管成熟和血脑屏障（BBB）的发育至关重要，但它们在维持成年血脑屏障中的作用，以及中枢神经系统周细胞与其他组织的区别，目前尚不清楚。我们发现叉头转录因子Foxf2在脑周细胞中特异性表达，Foxf2（-/-）胚胎出现颅内出血、血管周围水肿、血管基板变薄、管腔内皮小泡增加和血脑屏障渗漏。Foxf2（-/-）脑周细胞数量更多，增殖更快，Pdgfr β表达明显减少。Tgf - smad2 /3信号被减弱，而Smad1/5和p38的磷酸化被增强。Tgf β途径成分，包括Tgf β 2、Tgf β r2、Alk5和整合素α (V) β(8)减少。成人Foxf2失活导致血脑屏障破裂、内皮增厚和跨内皮囊泡运输增加。基于这些结果，FOXF2成为人类中风易感性的一个有趣的候选位点。
Pericytes are critical for cerebrovascular maturation and development of the blood-brain barrier (BBB), but their role in maintenance of the adult BBB, and how CNS pericytes differ from those of other tissues, is less well understood. We show that the forkhead transcription factor Foxf2 is specifically expressed in pericytes of the brain and that Foxf2(-/-) embryos develop intracranial hemorrhage, perivascular edema, thinning of the vascular basal lamina, an increase of luminal endothelial caveolae, and a leaky BBB. Foxf2(-/-) brain pericytes were more numerous, proliferated faster, and expressed significantly less Pdgfr beta. Tgf beta-Smad2/3 signaling was attenuated, whereas phosphorylation of Smad1/5 and p38 were enhanced. Tgf beta pathway components, including Tgf beta 2, Tgf beta r2, Alk5, and integrins alpha(V)beta(8), were reduced. Foxf2 inactivation in adults resulted in BBB breakdown, endothelial thickening, and increased trans-endothelial vesicular transport. On the basis of these results, FOXF2 emerges as an interesting candidate locus for stroke susceptibility in humans.