title: Tat 101-mediated enhancement of brain pericyte migration involves platelet-derived growth factor subunit B homodimer: implications for human immunodeficiency virus-associated neurocognitive disorders.
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.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Fang
authors.identifier: http://orcid.org/0000-0002-5035-7409
authors.initials: F
authors.lastname: Niu
authors.affiliation: Department of Pharmacology, Medical School of Southeast University, Nanjing, China, 210009, and.
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198.
authors.forename: Wenting
authors.identifier: http://orcid.org/0000-0002-6406-5220
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Emory University/Atlanta Veterans Affairs Medical Center, Atlanta, Georgia 30033.
authors.forename: Roy Lee
authors.initials: RL
authors.lastname: Sutliff
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198, sbuch@unmc.edu.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism*; D000328:Adult; D000818:Animals; D000077214:Becaplermin; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000821:virology; D015153:Blotting, Western; D001921:Brain; D002465:Cell Movement / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D015497:HIV-1; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D020286:Pericytes / Q000378:metabolism* / Q000821:virology*; D055503:Protein Multimerization; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D054322:tat Gene Products, Human Immunodeficiency Virus; D000077214:Becaplermin
keywords: BBB; HIV Tat; PDGF-BB; pericytes