PT  - JOURNAL ARTICLE
AU  - Fang Niu
AU  - Honghong Yao
AU  - Wenting Zhang
AU  - Roy Lee Sutliff
AU  - Shilpa Buch
TI  - Tat 101-Mediated Enhancement of Brain Pericyte Migration Involves Platelet-Derived Growth Factor Subunit B Homodimer: Implications for Human Immunodeficiency Virus-Associated Neurocognitive Disorders
AID  - 10.1523/JNEUROSCI.1139-14.2014
DP  - 2014 Aug 27
TA  - The Journal of Neuroscience
PG  - 11812--11825
VI  - 34
IP  - 35
4099  - http://www.jneurosci.org/content/34/35/11812.short
4100  - http://www.jneurosci.org/content/34/35/11812.full
SO  - J. Neurosci.2014 Aug 27; 34
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.