Endothelial Cells and Human Cerebral Small Vessel Disease

Abstract

Brain endothelial cells have unique properties in terms of barrier function, local molecular signaling, regulation of local cerebral blood flow (CBF) and interactions with other members of the neurovascular unit. In cerebral small vessel disease (arteriolosclerosis; SVD), the endothelial cells in small arteries survive, even when mural pathology is advanced and myocytes are severely depleted. Here, we review aspects of altered endothelial functions that have been implicated in SVD: local CBF dysregulation, endothelial activation and blood-brain barrier (BBB) dysfunction. Reduced CBF is reported in the diffuse white matter lesions that are a neuroradiological signature of SVD. This may reflect an underlying deficit in local CBF regulation (possibly via the nitric oxide/cGMP signaling pathway). While many laboratories have observed an association of symptomatic SVD with serum markers of endothelial activation, it is apparent that the origin of these circulating markers need not be brain endothelium. Our own neuropathology studies did not confirm local endothelial activation in small vessels exhibiting SVD. Local BBB failure has been proposed as a cause of SVD and associated parenchymal lesions. Some groups find that computational analyses of magnetic resonance imaging (MRI) scans, following systemic injection of a gadolinium-based contrast agent, suggest that extravasation into brain parenchyma is heightened in people with SVD. Our recent histochemical studies of donated brain tissue, using immunolabeling for large plasma proteins [fibrinogen, immunoglobulin G (IgG)], do not support an association of SVD with recent plasma protein extravasation. It is possible that a trigger leakage episode, or a size-selective loosening of the BBB, participates in SVD pathology.

Emerging Evidence for Pathogenesis of Sporadic Cerebral Small Vessel Disease

“…28 Hence, as demonstrated in the effects of salt and hypertension on endothelial dysfunction, VRFs may directly and indirectly cause endothelial dysfunction, and subsequent BBB breakdown can lead to enlarged perivascular spaces, cerebral microbleeds, and WM changes. 29 The 2 pathways described above do not occur in isolation but rather interact to exacerbate small vessel pathology, although the alternative pathway may contribute to a greater extent in the development of SVD. The fact that VRFs explain only ~2% of WMH variance 13 suggests that unconfirmed factors may contribute to small vessel pathology, such as WM disease.…”

“…Потребление соли также было ассо-циировано с воспалительной реакцией; у КСГПИ после употребления соли отметили значительное повышение содержания Е-селектина, воспалительного маркера, экс-прессируемого эндотелием, в головном мозге и сыворот-ке крови; однако у КСГ таких изменений не было [28]. Следовательно, как продемонстрировано воздействием соли и АГ на эндотелиальную дисфункцию, СФР могут прямо или косвенно быть причиной развития дисфунк-ции эндотелия, и последующее разрушение ГЭБ может приводить к расширению периваскулярных пространств, развитию церебральных микрокровоизлияний и измене-ний БВГМ [29].…”

Age-dependent expression of VEGFR2 in deep brain arteries in small vessel disease, CADASIL, and healthy brains

“…SVD is characterised by fibrotic thickening in the wall of small penetrating arteries, with depletion of vascular smooth muscle cells (VSMC) [18,25,26]. Though increasing age and high blood pressure are risk factors for SVD, the molecular drivers for these cellular changes are unknown.…”

The role of exercise in mitigating subcortical ischemic vascular cognitive impairment

“…Vascular lesions can include arteriolosclerosis, lipohyalinosis, fibrinoid necrosis, and small vessel atherosclerosis in perforating cerebral arterioles and capillaries (Sachdev et al 2014). Arteriolosclerosis is the most common form of SVD and is highly correlated with aging, hypertension, diabetes, and is directly associated with WMH (Erkinjuntti et al 1996;Schmidt et al 2004; van Swieten et al 1991;Hainsworth et al 2015). It is characterized by smooth muscle loss and collagenization of small arteries and arterioles.…”

“…The endothelium is a thin, flat cellular monolayer that lines the entire vascular tree. These cells have many important functions that include: (i) diffusion of oxygen and carbondioxide across capillary walls; (ii) sprouting and revascularization in response to cell signaling molecules such as vascular endothelial growth factor (VEGF) and forms of fibroblast growth factor, and (iii) autoregulation of local cerebral blood flow (CBF), which is a special feature of the brain vasculature (Hainsworth et al 2015). Autoregulation protects cerebral blood vessels from changes in arterial pressure associated with daily activities and provides a stable CBF baseline (Iadecola 2013).…”