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赛马福林6A相分离维持了在病理性血管生成中依赖于基因素乳酸的乳酸积累

Ya Ma¹, Zhuyi Zhang¹, Xiaolian Cao¹

¹Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.

Proceedings of the National Academy of Sciences of the United States of America

|April 17, 2025

概括

这项研究揭示了乳酸积累如何通过促进基因素乳化驱动缺血性视网膜疾病的病态血管生成. 针对这种途径,特别是Prmt5和Sema6A,抑制了新血管化,提供了新的治疗途径.

科学领域:

眼科医生眼科眼科
分子生物学分子生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

缺血视网膜疾病通过病理性血管生成导致失明.
内皮细胞 (EC) 的表观遗传变化,特别是从乳酸中激素的乳化,驱动了过度的血管生长.
在EC中调节组织乳酸的确切机制尚不清楚.

研究的目的:

阐明在病理性血管生成中组织素乳酸化的调节机制.
为了确定关键的分子参与者,参与维持质母乳化.
研究向这种途径在缺血性视网膜疾病中的治疗潜力.

主要方法:

在小鼠中利用氧气诱导的视网膜病变模型.
进行了联合CUT&Tag和单细胞RNA测序 (scRNA-seq) 分析.
为Prmt5和Sema6A生成了EC特定的淘汰模型.

主要成果:

在新血管EC中,乳酸盐积累诱导的基因组乳酸化 (H3K9la,H3K18la).
确定PRMT5是H3K9la和H3K18la的直接目标.
欧盟特异性Prmt5缺失通过破坏乳酸盐-氨酸乳酸化反循环来抑制血管生成.
证明SEMA6A的内在无序区域驱动相分离,招募RHOA和P300来促进基因素乳酸和PRMT5表达.
SEMA6A 除降低了基因素乳酸和PRMT5表达,抑制了新血管化.

结论:

建立了一个新的机制,其中SEMA6A介导的相分离通过P300激活维持了组织素乳化.
这一途径创建了一个积极的反循环,涉及乳酸,基因素乳酸和PRMT5,驱动病态血管生成.
向SEMA6A或PRMT5可能为治疗缺血视网膜疾病提供有效的策略.

关键词:

血管新生是因为血管新生.乳化乳化乳化阶段分离的分离阶段分离.视网膜视网膜视网膜是一个塞马福林是什么意思塞马福林是什么意思

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