Abstract
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.
Highlights
Cardiovascular diseases (CVD) such as atherosclerosis, hypertension and heart failure are all associated with an increased risk of vascular cognitive impairment (VCI)
Laser capture microdissection of human intra- vs. extracranial arterial endothelial cells (ECs) Analyses were performed on paired post-mortem derived ECs of the intracranial basilar artery (BA) and the extracranial common carotid artery (CCA)
In order to validate the selection of ECs and the differential expression between the BA and the CCA, we performed qPCR analysis of genes known to be highly expressed in intracranial ECs, such as Zona Occludens 1 (ZO1) and Endothelial Nitric Oxide Synthase 3 [6, 19]
Summary
Cardiovascular diseases (CVD) such as atherosclerosis, hypertension and heart failure are all associated with an increased risk of vascular cognitive impairment (VCI). Improvement of heart function or lowering of blood pressure is known to stimulate cognitive functioning [11, 23, 42]. Atherosclerosis is the most well-known disease of the arteries and is known to manifest itself differently in intracranial arteries compared to extracranial arteries. Intracranial atherosclerosis develops approximately 20 years later than extracranial atherosclerosis [57]. Intracranial atherosclerotic plaques are less advanced and less vulnerable to plaque rupture and intraplaque hemorrhages, compared to extracranial atherosclerotic plaques [31, 33, 44], suggesting a reduced susceptibility of intracranial arteries to systemic risk factors for atherosclerosis. Current research on VCI is focused on the vasculature in general
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