NOGOB receptor deficiency increases cerebrovascular permeability and hemorrhage via impairing histone acetylation–mediated CCM1/2 expression
Zhi Fang, … , Wenquan Hu, Qing Robert Miao
Zhi Fang, … , Wenquan Hu, Qing Robert Miao
Published March 22, 2022
Citation Information: J Clin Invest. 2022;132(9):e151382. https://doi.org/10.1172/JCI151382.
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Research Article Angiogenesis Vascular biology

NOGOB receptor deficiency increases cerebrovascular permeability and hemorrhage via impairing histone acetylation–mediated CCM1/2 expression

Abstract

The loss function of cerebral cavernous malformation (CCM) genes leads to most CCM lesions characterized by enlarged leaking vascular lesions in the brain. Although we previously showed that NOGOB receptor (NGBR) knockout in endothelial cells (ECs) results in cerebrovascular lesions in the mouse embryo, the molecular mechanism by which NGBR regulates CCM1/2 expression has not been elucidated. Here, we show that genetic depletion of Ngbr in ECs at both postnatal and adult stages results in CCM1/2 expression deficiency and cerebrovascular lesions such as enlarged vessels, blood-brain-barrier hyperpermeability, and cerebral hemorrhage. To reveal the molecular mechanism, we used RNA-sequencing analysis to examine changes in the transcriptome. Surprisingly, we found that the acetyltransferase HBO1 and histone acetylation were downregulated in NGBR-deficient ECs. The mechanistic studies elucidated that NGBR is required for maintaining the expression of CCM1/2 in ECs via HBO1-mediated histone acetylation. ChIP-qPCR data further demonstrated that loss of NGBR impairs the binding of HBO1 and acetylated histone H4K5 and H4K12 on the promotor of the CCM1 and CCM2 genes. Our findings on epigenetic regulation of CCM1 and CCM2 that is modulated by NGBR and HBO1-mediated histone H4 acetylation provide a perspective on the pathogenesis of sporadic CCMs.

Authors

Zhi Fang, Xiaoran Sun, Xiang Wang, Ji Ma, Thomas Palaia, Ujala Rana, Benjamin Miao, Louis Ragolia, Wenquan Hu, Qing Robert Miao

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Figure 1

The genetic depletion of Ngbr in ECs results in mouse brain hemorrhage and BBB disruption.

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The genetic depletion of Ngbr in ECs results in mouse brain hemorrhage a...
(A) Schedule of intraperitoneal tamoxifen injection in postnatal and adult Cdh5-CreERT2 Ngbrfl/fl (NgbrECKO) and Ngbrfl/fl mice at a dose of 75 mg/kg. (B and C) Representative images of whole-brain fresh tissue from postnatal and adult mice and H&E staining of brain sections. Blue arrows point to bleeding sites (B) and bleeding spots observed on H&E images (C) in the NgbrECKO group. Scale bars: 100 μm (low-magnification images) and 50 μm (high-magnification images). (D and E) Evans blue extravasation and brain water content are increased in the brain of postnatal and adult NgbrECKO mice. Data are presented as mean ± SD, n = 6 per group for postnatal mice and n = 5 per group for adult mice. Significance was tested by 2-tailed, unpaired Student’s t test. ***P < 0.001. (F) Representative images of immunofluorescent staining on 30-μm FITC-dextran–perfused brain sections showing vessel leakage in the NgbrECKO brain. ECs were labeled by CD31 immunostaining. Blue asterisks indicate the leaking sites. Scale bars: 100 μm. (G) Representative IgG staining images show IgG leakage into brain parenchyma in the brain of NgbrECKO mice. Black asterisks indicate leakage sites. Scale bars: 100 μm.