Fibroblast growth factor rescues brain endothelial cells lacking presenilin 1 from apoptotic cell death following serum starvation.

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.

早老素1（Psen1）对脑血管发育很重要，并且已知会影响细胞应激反应。为了解Psen1在内皮应激反应中的作用，我们研究了血清剥夺对野生型（wt）和Psen1 - / - 胚胎脑内皮细胞的影响。血清饥饿诱导Psen1 - / - 细胞凋亡，但不影响野生型细胞。血清饥饿的Psen1 - / - 细胞中PI3K/AKT信号通路减弱，这与磷酸化p38水平升高相关，这与在缺乏Psen1时促存活的AKT信号通路降低一致。成纤维细胞生长因子（FGF1和FGF2），而非血管内皮生长因子（VEGF）可使Psen1 - / - 细胞从血清饥饿诱导的凋亡中被挽救。在血清剥夺条件下，抑制FGF信号通路诱导野生型细胞凋亡，而阻断γ - 分泌酶活性则没有影响。在无血清情况下，FGF2免疫反应性在野生型和Psen1 - / - 细胞的细胞质和核小泡中弥散分布，因为细胞核和细胞质组分中FGF2的水平没有显著差异。因此，Psen1 - / - 细胞对血清饥饿的敏感性不是由于缺乏FGF合成，而可能是由于Psen1对FGF释放到细胞表面的影响以及PI3K/AKT存活通路的激活受损。