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

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 ( GSK3beta) activity. Using pharmacological approaches, gene transfer and kinase activity assays, we show that FGF2mediated angioprotection against gp120 toxicity is regulated by crosstalk among the ERK, PI3KAKT 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.