Molecular profiling of the stroke-induced alterations in the cerebral microvasculature reveals promising therapeutic candidates.
Molecular profiling of the stroke-induced alterations in the cerebral microvasculature reveals promising therapeutic candidates.
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DOI：
10.1073/pnas.2205786120
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发表时间：
2023-04-18
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
对脑卒中微血管功能障碍的分子机制的了解有限，是开发新治疗方法的主要障碍。在此，我们阐明了中风引起的小鼠脑微血管系统的转录组学变化，并将其与在人脑中风病变中观察到的变化进行了比较。我们的研究揭示了在微血管富集的、血管疾病相关的、可药物靶点中存在共同的改变，突出了脑微血管功能障碍在人类卒中病理生理学中的相关性。我们还确定了脑微血管中鞘脂代谢和信号传导途径的分子改变，这在人类中风中显著改变。我们的工作为将来研究脑卒中中新的内皮富集治疗候选药物提供了知识平台。脑卒中引起的脑微血管功能障碍导致神经元损伤加重，并影响目前再灌注治疗的疗效。了解脑卒中中脑微血管的分子改变将为新的治疗策略的科学研究提供原始的机会。为了实现这一目标，使用最近优化的方法，最大限度地减少细胞活化，并保留内皮细胞的相互作用和RNA的完整性，我们进行了全基因组的脑微血管的转录组分析在小鼠模型中风，并比较这些转录组的变化与人类，非致命性，脑中风病变中观察到的。这些无偏比较分析的结果揭示了小鼠中风微血管和人类中风病变的共同改变，并确定了与血管疾病相关的共同分子特征（例如，丝氨酸蛋白酶1/纤溶酶原激活物抑制剂-1，血红素加氧酶-1），内皮激活（例如，血管生成素-2），以及鞘脂代谢和信号传导的改变（例如，鞘氨醇-1-磷酸受体2）。小鼠脑微血管的鞘脂分析验证了转录数据，并揭示了脑微血管中鞘磷脂和鞘氨醇类物质的富集，与脑和脑卒中诱导的神经酰胺物质增加相比。总之，我们的研究已经确定了几个微血管富集的新的分子改变，相关的，和可药用的目标，这是内皮功能的有效调节剂。我们的比较分析揭示了人类慢性卒中病变中存在与脑微血管功能障碍相关的分子特征。这里分享的结果提供了一个详细的资源，为治疗发现候选人的神经血管保护中风和潜在的，其他病理表现出脑微血管功能障碍。
The limited understanding of the molecular mechanisms governing cerebral microvascular dysfunction in stroke has been a major obstacle in the development of novel therapeutic approaches. Herein, we elucidated the stroke-induced transcriptomic changes in the mouse cerebral microvasculature and compared them with the alterations observed in human brain stroke lesions. Our study revealed the presence of shared alterations in microvessel-enriched, vascular disease-associated, druggable targets, highlighting the relevance of cerebral microvascular dysfunction in human stroke pathophysiology. We have also identified molecular alterations in the sphingolipid metabolism and signaling pathway in the cerebral microvasculature, which were significantly altered in human stroke. Our work provides a knowledge platform for future investigation of novel endothelial-enriched therapeutic candidates in stroke. Stroke-induced cerebral microvascular dysfunction contributes to aggravation of neuronal injury and compromises the efficacy of current reperfusion therapies. Understanding the molecular alterations in cerebral microvessels in stroke will provide original opportunities for scientific investigation of novel therapeutic strategies. Toward this goal, using a recently optimized method which minimizes cell activation and preserves endothelial cell interactions and RNA integrity, we conducted a genome-wide transcriptomic analysis of cerebral microvessels in a mouse model of stroke and compared these transcriptomic alterations with the ones observed in human, nonfatal, brain stroke lesions. Results from these unbiased comparative analyses have revealed the common alterations in mouse stroke microvessels and human stroke lesions and identified shared molecular features associated with vascular disease (e.g., Serpine1/Plasminogen Activator Inhibitor-1, Hemoxygenase-1), endothelial activation (e.g., Angiopoietin-2), and alterations in sphingolipid metabolism and signaling (e.g., Sphigosine-1-Phosphate Receptor 2). Sphingolipid profiling of mouse cerebral microvessels validated the transcript data and revealed the enrichment of sphingomyelin and sphingoid species in the cerebral microvasculature compared to brain and the stroke-induced increase in ceramide species. In summary, our study has identified novel molecular alterations in several microvessel-enriched, translationally relevant, and druggable targets, which are potent modulators of endothelial function. Our comparative analyses have revealed the presence of molecular features associated with cerebral microvascular dysfunction in human chronic stroke lesions. The results shared here provide a detailed resource for therapeutic discovery of candidates for neurovascular protection in stroke and potentially, other pathologies exhibiting cerebral microvascular dysfunction.
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影响因子：
11.5
作者：
Akwii RG;Mikelis CM
通讯作者：
Mikelis CM
影响因子：
8.3
作者：
Chan SL;Bishop N;Li Z;Cipolla MJ
通讯作者：
Cipolla MJ
影响因子：
16.2
作者：
Cho C;Smallwood PM;Nathans J
通讯作者：
Nathans J
DOI：
10.3233/jad-2011-111202
发表时间：
2012
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Filippov V;Song MA;Zhang K;Vinters HV;Tung S;Kirsch WM;Yang J;Duerksen-Hughes PJ
通讯作者：
Duerksen-Hughes PJ
影响因子：
8.8
作者：
David S;Mukherjee A;Ghosh CC;Yano M;Khankin EV;Wenger JB;Karumanchi SA;Shapiro NI;Parikh SM
通讯作者：
Parikh SM