Brain Endothelial Hemostasis Regulation by Pericytes

Abstract

Pericytes are known to regulate brain capillary endothelial functions. The purpose of this study was to define the hemostatic regulatory role of human brain pericytes. We used blood-brain barrier models consisting of human pericytes grown on transwell membrane inserts and cocultured with human brain microvascular endothelial cells (HBEC), or pericytes grown in direct contact with HBEC. When grown in cocultures in which pericytes were physically separated from endothelial cells, pericytes induced significant changes in endothelial tissue plasminogen activator (tPA) messenger ribonucleic acid (mRNA) and protein: tPA mRNA level was decreased in pericyte cocultures (52%+/-25% of monocultures, P < 0.05) and tPA protein level was decreased (66%+/-23% of monocultures, P < 0.05). Pericyte effects on endothelial fibrinolysis were enhanced when the two cell types were cocultured in direct contact, with tPA protein reduced in cocultures compared with monocultures (25%+/-15% of monocultures, P < 0.05). Endotoxin (lipopolysaccharide (LPS)), used as a standardized stimulus to define brain-specific inflammation-induced change, amplified pericyte-induced enhanced release of the tPA inhibitor plasminogen activator inhibitor-1 (PAI-1); the latter was released by endothelial cells first cocultured with pericytes and then incubated with LPS in the absence of pericytes. Pericytes (in contrast to endothelial cells and astrocytes) were found to be the principal in vitro source of the serpin protease nexin-1 (PN-1), known to have primarily antithrombin effects. These in vitro findings suggest that pericytes negatively regulate brain endothelial cell fibrinolysis, while pericyte expression of PN-1 may provide endogenous anticoagulant activity.

Cerebral microvascular pericytes and neurogliovascular signaling in health and disease

“…Owing to their position between parenchyma and vessels, and their role in maintenance of the BBB, pericytes play important roles in leukocyte infiltration to the CNS (Daneman et al, 2010;Dohgu and Banks, 2013;Kim et al, 2006). Pericytes also present inflammatory cues and release inflammatory mediators including IL-1ș, IL-6, TNFȘ, ROS, NO and matrix metalloproteinases when activated with immune stimuli (Jansson et al, 2014;Kovac et al, 2011;Proebstl et al, 2012;Stark et al, 2013;Wang et al, 2012).…”

Cochlear Pericyte Responses to Acoustic Trauma and the Involvement of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor

“…30,34 We found that HIF-1␣ translocation and VEGF up-regulation also play a mediary role in noise-induced damage. Suppressing HIF-1␣ activity with sodium butyrate, a histone deacetylase inhibitor, 19,63 down-regulated VEGF at both the transcription and protein levels ( Figure 7). Pretreatment with an inhibitor for the VEGF receptor significantly reduced desmin expression ( Figure 8D).…”

“…11 The pericytes are known to have important roles in the regulation of vascular development, stabilization, maturation, and remodeling. [12][13][14][15][16][17][18][19][20] Pericytes also mediate physiological repair processes including adaptive responses that protect vulnerable tissues under stress. [21][22][23][24][25] Proliferation and recruitment of pericytes have frequently been found in ischemic tissues damaged by stroke.…”

Delivery of Neurotherapeutics Across the Blood Brain Barrier in Stroke

“…The BBB is composed principally of specialized capillary endothelial cells sealed by highly restrictive tight junctions not found elsewhere in the circulation. These endothelial cells are, in turn, surrounded by pericytes that cover 32% of the brain capillaries [3]. Pericytes synthesize most elements of the basement membrane and share this membrane with the endothelial cells.…”