Profiling the unique protective properties of intracranial arterial endothelial cells.

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.

Intraleaflet hemorrhages are a common finding in symptomatic aortic and mitral valves.

INTRODUCTION: Intraleaflet hemorrhage (ILH) has been reported to occur in calcified degenerated aortic valves. At present, no such information is available for mitral valves or for other types of valvular disease. We examined the prevalence, age, and potential source of ILH in a consecutive series of surgically removed aortic and mitral valves, and related the findings to specific types of heart valve pathology. METHODS: A total of 105 aortic (n=85) and mitral (n=20) valves were retrieved from 100 symptomatic patients. Pathological diagnosis was made on photographic images and histology. Presence, extent, and age of ILH; its possible association with calcification; microvessels; and microvascular leakage were assessed with conventional and immunohistochemical staining methods and related to the type of underlying valvular disease. RESULTS: Pathological diagnosis revealed degenerative aortic valve disease (n=70), postinflammatory disease (n=16), endocarditis (n=12), myxoid degenerative mitral valve disease (n=6), and one normal valve. ILH was found in 86% of aortic and 75% of mitral valves. Microvessels were present in 91% of all valves. Microvascular leakage was noted in 70% of aortic and 84% of mitral valves; in both groups, colocalization with ILH was found in 48%. Most aortic valves (91%) contained calcium deposits, of which 54% showed colocalization with ILH. In 66% of valves with ILH, a combination of recent hemorrhage and iron deposits was seen, indicating an ongoing process of episodic hemorrhages. CONCLUSION: The prevalence of ILH is very high in resected heart valves. Both aortic and mitral valves showed an association of ILH with microvessels, microvascular leakage, and calcifications. We speculate that repetitive microvascular-leakage-related ILH may contribute to valve dysfunction on the (very) long term.