Tat 101-mediated enhancement of brain pericyte migration involves platelet-derived growth factor subunit B homodimer

Implications for human immunodeficiency virus-associated neurocognitive disorders

Fang Niu, Honghong Yao, Wenting Zhang, Roy Lee Sutliff, Shilpa J Buch

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)11812-11825
Number of pages14
JournalJournal of Neuroscience
Volume34
Issue number35
DOIs
StatePublished - Aug 27 2014

Fingerprint

Proto-Oncogene Proteins c-sis
Pericytes
HIV
Brain
Blood-Brain Barrier
Microvessels
tat Gene Products
Platelet-Derived Growth Factor Receptors
Frontal Lobe
Viral Proteins
Encephalitis
Virus Replication
Neurocognitive Disorders
Mitogen-Activated Protein Kinases
Astrocytes
Endothelium
Cell Movement
HIV-1
Endothelial Cells

Keywords

  • BBB
  • HIV Tat
  • PDGF-BB
  • Pericytes

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Tat 101-mediated enhancement of brain pericyte migration involves platelet-derived growth factor subunit B homodimer : Implications for human immunodeficiency virus-associated neurocognitive disorders. / Niu, Fang; Yao, Honghong; Zhang, Wenting; Sutliff, Roy Lee; Buch, Shilpa J.

In: Journal of Neuroscience, Vol. 34, No. 35, 27.08.2014, p. 11812-11825.

Research output: Contribution to journalArticle

@article{b66ea4a5c8554ebb9b8edf99c7e131ec,
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.",
keywords = "BBB, HIV Tat, PDGF-BB, Pericytes",
author = "Fang Niu and Honghong Yao and Wenting Zhang and Sutliff, {Roy Lee} and Buch, {Shilpa J}",
year = "2014",
month = "8",
day = "27",
doi = "10.1523/JNEUROSCI.1139-14.2014",
language = "English (US)",
volume = "34",
pages = "11812--11825",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "35",

}

TY - JOUR

T1 - Tat 101-mediated enhancement of brain pericyte migration involves platelet-derived growth factor subunit B homodimer

T2 - Implications for human immunodeficiency virus-associated neurocognitive disorders

AU - Niu, Fang

AU - Yao, Honghong

AU - Zhang, Wenting

AU - Sutliff, Roy Lee

AU - Buch, Shilpa J

PY - 2014/8/27

Y1 - 2014/8/27

N2 - 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.

AB - 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.

KW - BBB

KW - HIV Tat

KW - PDGF-BB

KW - Pericytes

UR - http://www.scopus.com/inward/record.url?scp=84906545643&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906545643&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.1139-14.2014

DO - 10.1523/JNEUROSCI.1139-14.2014

M3 - Article

VL - 34

SP - 11812

EP - 11825

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 35

ER -