UNASSIGNED: Transcriptomic analysis of human brain pericytes with ALK5 silencing identified differential gene expression. Brain vascular cells isolated from mutant embryonic mice with GMH-IVH and preterm human IVH brain samples were utilized for target validation. Finally, pharmacological and genetic inhibition was used to study the therapeutic effects on GMH-IVH pathology.
UNASSIGNED: Herein, we establish that the TGFβ/ALK5 pathway robustly represses ANGPT2 (angiopoietin-2) in pericytes via epigenetic remodeling. TGFβ-driven SMAD (suppressor of mothers against decapentaplegic) 3/4 associates with TGIF1 (TGFβ-induced factor homeobox 1) and HDAC (histone deacetylase) 5 to form a corepressor complex at the Angpt2 promoter, resulting in promoter deacetylation and gene repression. Moreover, murine and human germinal matrix vessels display increased ANGPT2 expression during GMH-IVH. Isolation of vascular cells from murine germinal matrix identifies pericytes as a cellular source of excessive ANGPT2. In addition, mutant endothelial cells exhibit higher phosphorylated TIE2 (tyrosine protein kinase receptor). Pharmacological or genetic inhibition of ANGPT2 in mutants improves germinal matrix vessel morphology and attenuates GMH pathogenesis. Importantly, genetic ablation of Angpt2 in mutant pericytes prevents perinatal lethality, prolonging survival.
UNASSIGNED: This study demonstrates that TGFβ-mediated ANGPT2 repression in pericytes is critical for maintaining blood-brain barrier integrity and identifies pericyte-derived ANGPT2 as an important pathological target for GMH-IVH.
■使用ALK5沉默的人脑周细胞的转录组学分析鉴定了差异基因表达。从具有GMH-IVH的突变胚胎小鼠和早产人IVH脑样品中分离的脑血管细胞用于靶标验证。最后,药理学和遗传抑制用于研究对GMH-IVH病理的治疗作用。
■这里,我们确定TGFβ/ALK5途径通过表观遗传重塑强烈抑制周细胞中的ANGPT2(血管生成素-2)。TGFβ驱动的SMAD(母亲对十性截瘫的抑制作用)3/4与TGIF1(TGFβ诱导的同源异型盒1)和HDAC(组蛋白脱乙酰酶)5结合,在Angpt2启动子处形成共阻遏复合物,导致启动子脱乙酰和基因抑制。此外,鼠和人生发基质血管在GMH-IVH期间显示ANGPT2表达增加。从鼠生发基质中分离血管细胞将周细胞鉴定为过量ANGPT2的细胞来源。此外,突变的内皮细胞表现出更高的磷酸化TIE2(酪氨酸蛋白激酶受体)。突变体中ANGPT2的药理学或遗传学抑制改善生发基质血管形态并减弱GMH发病机理。重要的是,突变周细胞中Angpt2的遗传消融可防止围产期致死,延长生存期。
■该研究表明,周细胞中TGFβ介导的ANGPT2抑制对于维持血脑屏障完整性至关重要,并将周细胞衍生的ANGPT2确定为GMH-IVH的重要病理靶标。