Genetic deletion of microRNA-15a/16-1 in pericytes stimulates cerebral angiogenesis and promotes functional recovery after ischemic stroke.

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
Ping Sun, Yang Xu, Tianqing Xiong, Shun Li, Na Qiu, Chao Zhou, Jiefei Wang, Alexander Chang, Uma R Chandran, Ke-Jie Yin
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引用次数: 0

Abstract

Stroke is a leading cause of mortality and disability globally. Despite advancements in acute stroke therapies, patient outcomes with ischemic stroke remain suboptimal. Understanding its molecular mechanisms is crucial for developing effective treatments. Angiogenesis actively contributes to post-stroke functional recovery and improves long-term survival in stroke patients. Pericytes are essential for maintaining vascular stability and promoting angiogenesis. We hypothesized that microRNA-15a/16-1 in pericytes significantly modulates post-stroke angiogenesis and neurological recovery. Using a pericyte-specific miR-15a/16-1 conditional knockout (cKO) mouse model, we found that genetic deletion of miR-15a/16-1 in pericytes enhances angiogenesis, promotes cerebral blood flow recovery, and improves sensorimotor and cognitive outcomes following ischemic stroke. Mechanistically, RNA sequencing identified several novel targets of miR-15a/16-1, including Pappa2, Fgf9, Islr, and Ccr2. Interestingly, Pappa2, Fgf9, and Islr function as secreted proteins. Luciferase reporter assays demonstrated that miR-15a/16-1 directly binds and suppresses Pappa2, Fgf9, Islr, and Ccr2 activity in cultured pericytes. In vivo and in vitro assays further confirmed that miR-15a/16-1 silencing in pericytes significantly elevates the protein levels of Pappa2, Fgf9, Islr, and Ccr2 and enhances endothelial cell proliferation, migration, and tube formation under ischemic conditions. These findings suggest that targeting miR-15a/16-1 in pericytes offers a promising therapeutic strategy for enhancing stroke recovery by promoting neurovascular repair and reducing brain damage.

周细胞中microRNA-15a/16-1基因缺失刺激脑血管新生,促进缺血性脑卒中后功能恢复。
中风是全球死亡和残疾的主要原因。尽管急性脑卒中治疗取得了进展,但缺血性脑卒中患者的预后仍然不理想。了解其分子机制对于开发有效的治疗方法至关重要。血管生成积极促进脑卒中后功能恢复,提高脑卒中患者的长期生存率。周细胞对维持血管稳定和促进血管生成至关重要。我们假设周细胞中的microRNA-15a/16-1显著调节脑卒中后血管生成和神经恢复。使用周细胞特异性miR-15a/16-1条件敲除(cKO)小鼠模型,我们发现周细胞中miR-15a/16-1的基因缺失可增强血管生成,促进脑血流恢复,并改善缺血性卒中后的感觉运动和认知结果。在机制上,RNA测序鉴定了miR-15a/16-1的几个新靶点,包括Pappa2、Fgf9、Islr和Ccr2。有趣的是,Pappa2、Fgf9和Islr作为分泌蛋白发挥作用。荧光素酶报告基因检测表明,miR-15a/16-1直接结合并抑制培养周细胞中Pappa2、Fgf9、Islr和Ccr2的活性。体内和体外实验进一步证实,在缺血条件下,周细胞中miR-15a/16-1沉默可显著提高Pappa2、Fgf9、Islr和Ccr2的蛋白水平,增强内皮细胞的增殖、迁移和小管形成。这些发现表明,通过促进神经血管修复和减少脑损伤,靶向周细胞中的miR-15a/16-1提供了一种有希望的治疗策略,可以增强中风的恢复。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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