Abstract
Presenilin 1 (Psen1) is important for vascular brain development and is known to influence cellular stress responses. To understand the role of Psen1 in endothelial stress responses, we investigated the effects of serum withdrawal on wild type (wt) and Psen1−/− embryonic brain endothelial cells. Serum starvation induced apoptosis in Psen1−/− cells but did not affect wt cells. PI3K/AKT signaling was reduced in serum-starved Psen1−/− cells, and this was associated with elevated levels of phospho-p38 consistent with decreased pro-survival AKT signaling in the absence of Psen1. Fibroblast growth factor (FGF1 and FGF2), but not vascular endothelial growth factor (VEGF) rescued Psen1−/− cells from serum starvation induced apoptosis. Inhibition of FGF signaling induced apoptosis in wt cells under serum withdrawal, while blocking γ-secretase activity had no effect. In the absence of serum, FGF2 immunoreactivity was distributed diffusely in cytoplasmic and nuclear vesicles of wt and Psen1−/− cells, as levels of FGF2 in nuclear and cytosolic fractions were not significantly different. Thus, sensitivity of Psen1−/− cells to serum starvation is not due to lack of FGF synthesis but likely to effects of Psen1 on FGF release onto the cell surface and impaired activation of the PI3K/AKT survival pathway.
Highlights
Embryonic brain, Psen[1] deficiency in endothelial cells results in decreased turnover of the extracellular matrix protein fibronectin[14]
We found that whereas wt brain endothelial cells could withstand serum starvation, Presenilin 1 (Psen1)−/−endothelial cells rapidly underwent apoptosis following serum withdrawal
We investigated whether fibroblast growth factors (FGFs) could protect Psen1−/−cells from apoptosis induced by serum deprivation
Summary
Embryonic brain, Psen[1] deficiency in endothelial cells results in decreased turnover of the extracellular matrix protein fibronectin[14]. Presenilins and presenilin FAD mutants have long been known to influence stress responses in cells including sensitivity to apoptosis[15,16,17,18,19,20]. To understand the role of Psen[1] in endothelial cells, we analyzed the response of embryonic brain endothelial cells to a stress signal generated by serum withdrawal. We show that serum starvation of Psen1−/−brain endothelial cells leads to their detachment from a collagen type IV substrate and apoptosis, but does not significantly affect the viability or attachment of wild-type (wt) brain endothelial cells. Using serum- and supplement-free media we show that either acidic or basic fibroblast growth factors (FGFs) are able to rescue brain endothelial cells from apoptotic cell death following serum starvation, whereas vascular endothelial cell growth factor (VEGF) cannot
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