Advances in the Role of Endothelial Cells in Cerebral Small Vessel Disease

Abstract

Cerebral small vessel disease (CSVD) poses a serious socio-economic burden due to its high prevalence and severe impact on the quality of life of elderly patients. Pathological changes in CSVD mainly influence small cerebral arteries, microarteries, capillaries, and small veins, which are usually caused by multiple vascular risk factors. CSVD is often identified on brain magnetic resonance imaging (MRI) by recent small subcortical infarcts, white matter hyperintensities, lacune, cerebral microbleeds (CMBs), enlarged perivascular spaces (ePVSs), and brain atrophy. Endothelial cell (EC) dysfunction is earlier than clinical symptoms. Immune activation, inflammation, and oxidative stress may be potential mechanisms of EC injury. ECs of the blood-brain-barrier (BBB) are the most important part of the neurovascular unit (NVU) that ensures constant blood flow to the brain. Impaired cerebral vascular autoregulation and disrupted BBB cause cumulative brain damage. This review will focus on the role of EC injury in CSVD. Furthermore, several specific biomarkers will be discussed, which may be useful for us to assess the endothelial dysfunction and explore new therapeutic directions.

Keywords: blood-brain barrier; cerebral small vessel disease (CSVD); cognitive impairment; endothelial cells (ECs); hypertension; white matter hyperintensities (WMH).

Figure 1

The typical manifestation of cerebral small vessel disease (CSVD) on MRI.

Figure 2

The structure of blood–brain barrier (BBB) and neurovascular unit (NVU). BBB regulates substance influx and efflux to ensure a homeostatic environment for the brain function, which is composed by basement membrane, astrocytes, and endothelial cells (ECs) anchored to each others by tight junction. Neurones, interneurones, astrocytes, smooth muscular cells, pericytes, and ECs are important constituents of NVU, which provides a basic structure for NVC and regulates the cerebral blood flow (CBF).

Figure 3

Graphic abstract of this review.

Figure 4

Physiological functions of Endocan. The yellow squares at the upper or lower edges represent ECs, which form vascular endothelium by tight junctions; the red hollow circles represent red blood cells; the light blue circles represent leukocytes; the yellow squares with black borders represent platelets. (1) Endocan regulates the interaction between ECs and leukocytes. (2) Endocan promotes the expression of vascular endothelial growth factor-A (VEGF-A) and enhances the binding of VEGF-A to its receptors. The activation of a VEGF signaling pathway contributes to the production of Endocan. (3) Endocan promotes the release of pro-inflammatory substances.