Emerging roles of pericytes in the regulation of the neurovascular unit in health and disease

Abstract

Pericytes of the central nervous system (CNS) are uniquely positioned within a multicellular structure termed the neurovascular unit (NVU) to provide crucial support to blood brain barrier (BBB) formation, maintenance, and stability. Numerous CNS diseases are associated with some aspect of BBB dysfunction. A dysfunction can manifest as one or multiple disruptions to any of the following barriers: physical, metabolic, immunological and transport barrier. A breach in the BBB can notably result in BBB hyper-permeability, endothelial activation and enhanced immune-endothelial interaction. How the BBB is regulated within this integrated unit remains largely unknown, especially as it relates to pericyte-endothelial interaction. We summarize the latest findings on pericyte origin, possible marker expression, and availability within different organ systems. We highlight pericyte-endothelial cell interactions, concentrating on extra- and intra- cellular signaling mechanisms linked to platelet derived growth factor-B, transforming growth factor -β, angiopoietins, Notch, and gap junctions. We discuss the role of pericytes in the NVU under inflammatory insult, focusing on how pericytes may indirectly affect leukocyte CNS infiltration, the direct role of pericyte-mediated basement membrane modifications, and immune responses. We review new findings of pericyte actions in CNS pathologies including Alzheimer's disease, stroke, multiple sclerosis, diabetic retinopathy, and HIV-1 infection. The uncovering of the regulatory role of pericytes on the BBB will provide key insight into how barrier integrity can be re-established during neuroinflammation.

Figure 1

Decrease of pericyte coverage of the BBB in HIV-1 infected patients. (A,C) Strong contiguous staining for PDGF-Rβ (green) was found in control brains corresponding to the endothelial lining (Ulex europeus, red) (B,D). (E,G) In HIV cases, there was noticeable diminution in PDGF-Rβ labeling of pericytes (green), confirmed by double staining for endothelial cells (Ulex europeus, red) (F,H). Arrows indicate the same microvessels in double-stained PDGF-Rβ (green)/Ulex (red) panels: A/B, C/D, E/F, G/H. Original magnification: A,B,E,F ×200; C,D,G,H ×400. Scale bar =50 mm

Figure 2

Altered tight junctions (TJ) and diminished pericyte coverage in HIV-1-infected patients. (A) There was no p-occludin staining (green) detecting compromised TJ in microvessels of control brain tissue, with strong CD13 (pericyte marker, red, B). (D) Microvessels in HIV-1 brains (even without HIVE) featured p-occludin (green) and diminution of CD13 (red, E). Panels C and F are overlays of A/B and D/E. Original magnification: A-F ×400. Scale bar =50 mm

Figure 3

Decreased claudin-5 staining and diminished pericyte coverage in HIV-infected ‘humanized’ NSG mice. NOD.Cg-Prkdc^scid Il2rg^tm1Wjl /SzJ, huNSG mice (reconstituted with CD34⁺ cells at birth) were infected with HIV-1 demonstrating sustained viremia (350,000 copies/mL, over 3 months period). (A) Contiguous strong staining for PDGF-Rβ (red) was found in pericytes in control mice without HIV-1 infection (A,G) and paralleling uniform expression of claudin-5 (green, D,G). There was obvious down-regulation or even disappearance of PDGF-Rβ (red) in HIV-infected animals (B,C,H,I) and uneven staining for claudin 5 (green) in the same microvessels (E,F,H,I). Panel G is the overlay for A/D, H for panels B/E, and I for panels C/F. Original magnification: A-I ×400. Scale bar =50 mm. Arrows indicate the same microvessels in double-stained panels

Figure 4

Pericyte-brain endothelial cell interactions under physiologic conditions (A) and HIV-1 infection/chronic inflammation (B)