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Open Access Research article

Signalling crosstalk in FGF2-mediated protection of endothelial cells from HIV-gp120

Dianne Langford1*, Rosemary Hurford2, Makoto Hashimoto2, Murat Digicaylioglu3 and Eliezer Masliah12

Author Affiliations

1 Department of Pathology, University of California, San Diego, La Jolla, CA, USA

2 Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA

3 The Burnham Institute Center for Neuroscience and Aging, La Jolla, CA, USA

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BMC Neuroscience 2005, 6:8  doi:10.1186/1471-2202-6-8

Published: 2 February 2005

Abstract

Background

The blood brain barrier (BBB) is the first line of defence of the central nervous system (CNS) against circulating pathogens, such as HIV. The cytotoxic HIV protein, gp120, damages endothelial cells of the BBB, thereby compromising its integrity, which may lead to migration of HIV-infected cells into the brain. Fibroblast growth factor 2 (FGF2), produced primarily by astrocytes, promotes endothelial cell fitness and angiogenesis. We hypothesized that treatment of human umbilical vein endothelial cells (HUVEC) with FGF2 would protect the cells from gp120-mediated toxicity via endothelial cell survival signalling.

Results

Exposure of HUVEC to gp120 resulted in dose- and time-dependent cell death; whereas, pre-treatment of endothelial cells with FGF2 protected cells from gp120 angiotoxicity. Treatment of HUVEC with FGF2 resulted in dose- and time-dependent activation of the extracellular regulated kinase (ERK), with moderate effects on phosphoinositol 3 kinase (PI3K) and protein kinase B (PKB), also known as AKT, but no effects on glycogen synthase kinase 3 (GSK3β) activity. Using pharmacological approaches, gene transfer and kinase activity assays, we show that FGF2-mediated angioprotection against gp120 toxicity is regulated by crosstalk among the ERK, PI3K-AKT and PKC signalling pathways.

Conclusions

Taken together, these results suggest that FGF2 may play a significant role in maintaining the integrity of the BBB during the progress of HIV associated cerebral endothelial cell damage.