Cardiovascular disorders, like atherosclerosis and hypertension, are increasingly known to be associated with vascular cognitive impairment (VCI). In particular, intracranial atherosclerosis is one of the main causes of VCI, although plaque development occurs later in time and is structurally different compared to atherosclerosis in extracranial arteries. Recent data suggest that endothelial cells (ECs) that line the intracranial arteries may exert anti-atherosclerotic effects due to yet unidentified pathways. To gain insights into underlying mechanisms, we isolated post-mortem endothelial cells from both the intracranial basilar artery (BA) and the extracranial common carotid artery (CCA) from the same individual (total of 15 individuals) with laser capture microdissection. RNA sequencing revealed a distinct molecular signature of the two endothelial cell populations of which the most prominent ones were validated by means of qPCR. Our data reveal for the first time that intracranial artery ECs exert an immune quiescent phenotype. Secondly, genes known to be involved in the response of ECs to damage (inflammation, differentiation, adhesion, proliferation, permeability and oxidative stress) are differentially expressed in intracranial ECs compared to extracranial ECs. Finally, Desmoplakin (DSP) and Hop Homeobox (HOPX), two genes expressed at a higher level in intracranial ECs, and Sodium Voltage-Gated Channel Beta Subunit 3 (SCN3B), a gene expressed at a lower level in intracranial ECs compared to extracranial ECs, were shown to be responsive to shear stress and/or hypoxia. With our data we present a set of intracranial-specific endothelial genes that may contribute to its protective phenotype, thereby supporting proper perfusion and consequently may preserve cognitive function. Deciphering the molecular regulation of the vascular bed in the brain may lead to the identification of novel potential intervention strategies to halt vascular associated disorders, such as atherosclerosis and vascular cognitive dysfunction.

中文翻译：

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分析颅内动脉内皮细胞的独特保护特性。

越来越多地发现诸如动脉粥样硬化和高血压之类的心血管疾病与血管性认知障碍（VCI）相关。尤其是，颅内动脉粥样硬化是VCI的主要原因之一，尽管斑块发育发生的时间较晚，并且与颅外动脉中的动脉粥样硬化相比在结构上有所不同。最新数据表明，由于尚不清楚的途径，位于颅内动脉的内皮细胞（EC）可能发挥抗动脉粥样硬化作用。为了深入了解潜在的机制，我们通过激光捕获显微解剖从同一个人（共15个人）从颅内基底动脉（BA）和颅外颈总动脉（CCA）分离了死后内皮细胞。RNA测序揭示了两个内皮细胞群的独特分子特征，其中最突出的是通过qPCR验证的。我们的数据首次揭示了颅内动脉ECs具有免疫静止表型。其次，与颅外EC相比，已知与EC对损伤的反应（炎症，分化，粘附，增殖，通透性和氧化应激）有关的基因在颅内EC中差异表达。最后，Desmoplakin（DSP）和Hop Homeobox（HOPX）这两个基因在颅内EC中表达较高，而钠电压门控通道Beta亚基3（SCN3B）在颅内EC中表达较颅外水平低。 ECs被证明对剪切应力和/或缺氧有反应。根据我们的数据，我们提出了一组颅内特异性内皮基因，可能有助于保护性表型，从而支持适当的灌注，因此可能保留认知功能。破译脑血管床的分子调控可能导致鉴定新颖的潜在干预策略，以停止与血管相关的疾病，例如动脉粥样硬化和血管认知功能障碍。