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Profiling the unique protective properties of intracranial arterial endothelial cells
Dorien M A Hermkens1, Olga C G Stam2, Nienke M de Wit3
1Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, Netherlands. d.m.hermkens@amsterdamumc.nl.
Insights
Intracranial artery endothelial cells (ECs) have a unique, immune-quiet profile, unlike those in extracranial arteries. This study identifies specific genes in brain artery ECs that may protect against atherosclerosis and preserve cognitive function.
Area of Science:
- Neuroscience
- Vascular Biology
- Genomics
Background:
- Cardiovascular disorders, including atherosclerosis and hypertension, are linked to vascular cognitive impairment (VCI).
- Intracranial atherosclerosis is a primary cause of VCI, with distinct plaque characteristics compared to extracranial atherosclerosis.
- Endothelial cells (ECs) in intracranial arteries may possess protective anti-atherosclerotic properties via unknown mechanisms.
Purpose of the Study:
- To investigate the molecular differences between intracranial and extracranial artery ECs.
- To identify genes and pathways contributing to the protective phenotype of intracranial ECs.
- To explore potential therapeutic targets for VCI and related vascular disorders.
Main Methods:
- Isolation of post-mortem endothelial cells from the basilar artery (intracranial) and common carotid artery (extracranial) using laser capture microdissection.
- RNA sequencing to compare gene expression profiles between intracranial and extracranial ECs.
- Quantitative PCR (qPCR) to validate key gene expression findings.
Main Results:
- Intracranial ECs exhibit a distinct molecular signature, characterized by an immune-quiescent phenotype.
- Genes involved in EC damage responses (inflammation, differentiation, adhesion, permeability, oxidative stress) are differentially expressed.
- Specific genes, including Desmoplakin (DSP), Hop Homeobox (HOPX), and Sodium Voltage-Gated Channel Beta Subunit 3 (SCN3B), show differential expression and responsiveness to shear stress/hypoxia.
Conclusions:
- Intracranial ECs possess unique genetic profiles that may confer protection against atherosclerosis.
- These findings highlight potential mechanisms for preserving brain perfusion and cognitive function.
- Understanding intracranial EC regulation offers novel intervention strategies for vascular cognitive dysfunction.
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.
