軍事醫(yī)學科學院生物工程研究所發(fā)育與疾病遺傳研究室主任楊曉研究員是國內(nèi)著名的基因敲除研究專家。近期,，她領導的研究小組利用基因敲除技術研究了TGF-β信號通路的核心信號轉(zhuǎn)導分子Smad4在調(diào)控大腦血管內(nèi)皮細胞功能中的作用,。相關研究論文發(fā)表在國際著名期刊《細胞》（Cell）旗下的子刊《發(fā)育細胞》（Developmental cell）雜志上。
在臨床上,，腦功能障礙常與新生兒顱內(nèi)出血（ICH）和成人中風有著密切的關系,。腦血管內(nèi)皮細胞(ECs)通過與周圍細胞交互作用在中樞神經(jīng)系統(tǒng)中發(fā)揮維持腦循環(huán)穩(wěn)定的重要功能。然而目前對于調(diào)控大腦血管內(nèi)皮細胞功能的遺傳機制仍然知之甚少,。
轉(zhuǎn)化生長因子-β(TGF-β)是一個包括數(shù)十種TGF-βs,、骨形態(tài)發(fā)生蛋白(BMPs)等配體在內(nèi)的生長因子超家族。近年來大量的研究表明TGF-β信號通路控制著一系列的細胞反應,，包括細胞增殖,、分化、細胞外基質(zhì)重建和胚胎發(fā)育,。TGF-β信號轉(zhuǎn)導異常與多種疾病如腫瘤的起始和轉(zhuǎn)移,、組織纖維化，自身免疫性疾病及心腦血管疾病有關,。
為了更深入地研究核心信號轉(zhuǎn)導分子Smad4介導的TGF-β信號在腦血管系統(tǒng)發(fā)育和穩(wěn)態(tài)中的作用,，研究人員特異性地敲除了小鼠腦血管內(nèi)皮細胞中Smad4基因，發(fā)現(xiàn)Smad4缺陷可導致新生小鼠發(fā)生顱內(nèi)出血和血腦屏障異常,。在進一步的研究中,，她們證實Smad4是通過在N-cadherin啟動子RBP-J結合點上與Notch胞內(nèi)復合物結合調(diào)控N-cadherin的轉(zhuǎn)錄從而發(fā)揮穩(wěn)定腦血管內(nèi)皮細胞與周圍細胞之間相互作用的功能。
新發(fā)現(xiàn)揭示了Smad4在維持腦血管穩(wěn)定性上特殊功能,，表明TGF-β/Smad信號遺傳或功能缺陷與腦血管功能障礙性疾病的發(fā)病有著重要的相關性,。（生物谷Bioon.com）
生物谷推薦原文出處：
Developmental Cell doi:10.1016/j.devcel.2011.01.011
Endothelial Smad4 Maintains Cerebrovascular Integrity by Activating N-Cadherin through Cooperation with Notch
Fangfei Li, Yu Lan, Youliang Wang, Jun Wang, Guan Yang, Fanwei Meng, Hua Han, Anming Meng, Yaping Wang, Xiao Yang
Highlights
Smad4 loss in brain endothelial cells (ECs) causes neonatal intracranial hemorrhage
Endothelial Smad4 stabilizes cerebrovascular EC-pericyte interactions via N-cadherin
TGF-β/BMP and Notch pathways cooperatively upregulate N-cadherin in ECs
Summary
Cerebrovascular dysfunction is strongly associated with neonatal intracranial hemorrhage (ICH) and stroke in adults. Cerebrovascular endothelial cells (ECs) play important roles in maintaining a stable cerebral circulation in the central nervous system by interacting with pericytes. However, the genetic mechanisms controlling the functions of cerebral ECs are still largely unknown. Here, we report that disruption of Smad4, the central intracellular mediator of transforming growth factor-β (TGF-β) signaling, specifically in the cerebral ECs, results in perinatal ICH and blood-brain barrier breakdown. Furthermore, the mutant vessels exhibit defective mural cell coverage. Smad4 stabilizes cerebrovascular EC-pericyte interactions by regulating the transcription of N-cadherin through associating with the Notch intracellular complex at the RBP-J binding site of the N-cadherin promoter. These findings uncover a distinct role of endothelial Smad4 in maintaining cerebrovascular integrity and suggest important implications for genetic or functional deficiencies in TGF-β/Smad signaling in the pathogenesis of cerebrovascular dysfunction.
