Tat 101-mediated enhancement of brain pericyte migration involves platelet-derived growth factor subunit B homodimer: implications for human immunodeficiency virus-associated neurocognitive disorders.

TitleTat 101-mediated enhancement of brain pericyte migration involves platelet-derived growth factor subunit B homodimer: implications for human immunodeficiency virus-associated neurocognitive disorders.
Publication TypeJournal Article
Year of Publication2014
AuthorsNiu, F, Yao, H, Zhang, W, Sutliff, RLee, Buch, S
JournalJ Neurosci
Volume34
Issue35
Pagination11812-25
Date Published2014 Aug 27
ISSN1529-2401
KeywordsAdult, AIDS Dementia Complex, Animals, Blood-Brain Barrier, Blotting, Western, Brain, Cell Movement, External, Female, Fluorescent Antibody Technique, HIV-1, Humans, Immunohistochemistry, Immunoprecipitation, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Pericytes, Protein Multimerization, Proto-Oncogene Proteins c-sis, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, tat Gene Products, Human Immunodeficiency Virus, Transfection
Abstract

In the era of antiretroviral therapy, although the human immunodeficiency virus (HIV) replication can be successfully controlled, complications of the CNS continue to affect infected individuals. Viral Tat protein is not only neurotoxic but has also been shown to disrupt the integrity of the blood-brain barrier (BBB). Although the role of brain microvascular endothelial cells and astrocytes in Tat-mediated impairment has been well documented, pericytes, which are important constituents of the BBB and play a key role in maintaining the integrity of the barrier, remain poorly studied in the context of HIV-associated neurocognitive disorders (HAND). In the present study, we demonstrated that exposure of human brain microvascular pericytes and C3H/10T1/2 cells to HIV-1 Tat101 resulted in increased expression of platelet-derived growth factor subunit B homodimer (PDGF-BB) and increased migration of the treated cells. Furthermore, we also demonstrated that this effect of Tat was mediated via activation of mitogen-activated protein kinases and nuclear factor-κB pathways. Secreted PDGF-BB resulted in autocrine activation of the PDGF-BB/PDGF β receptor signaling pathway, culminating ultimately into increased pericyte migration. Ex vivo relevance of these findings was further corroborated in isolated microvessels of HIV Tg26 mice that demonstrated significantly increased expression of PDGF-BB in isolated brain microvessels with a concomitant loss of pericytes. Intriguingly, loss of pericyte coverage was also detected in sections of frontal cortex from humans with HIV-encephalitis compared with the uninfected controls. These findings thus implicate a novel role of PDGF-BB in the migration of pericytes, resulting in loss of pericyte coverage from the endothelium with a subsequent breach of the BBB.

DOI10.1523/JNEUROSCI.1139-14.2014
Alternate JournalJ. Neurosci.
PubMed ID25164676
PubMed Central IDPMC4145180
Grant ListDA033150 / DA / NIDA NIH HHS / United States
DA033614 / DA / NIDA NIH HHS / United States
DA035203 / DA / NIDA NIH HHS / United States
DA036157 / DA / NIDA NIH HHS / United States
P30 MH062261 / MH / NIMH NIH HHS / United States