Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, V5Z 1L3 BC, Canada.
Microvasc Res. 2013 Sep;89:80-5. doi: 10.1016/j.mvr.2013.05.007. Epub 2013 Jun 3.
Loss of endothelial viability correlates with initiation and progress of vascular pathology. However, much remains to be learned about pathways required to maintain the balance between cell viability and apoptosis. Notch activation can enhance or inhibit apoptosis but its role in maintaining the endothelium needs further delineation.
This study aims to identify the mechanisms by which Notch activation regulates endothelial viability.
Endothelial cells transduced with active Notch were treated with lipopolysaccharide (LPS) or homocysteine to induce endothelial apoptosis. Notch protected against LPS-induced cell death but exacerbated homocysteine-induced apoptosis. Inhibition of PI3K revealed that ligand-induced activation of endogenous Notch initiates parallel death and survival pathways and exhibits a differential effect on endothelial survival depending on the apoptotic stimulus. PI3K activity regulated the expression of Slug, which was required for survival in Notch-activated endothelial cells. Homocysteine, but not LPS, blocked both PI3K activity and Slug expression in Notch-activated cells, leading to increased endothelial apoptosis.
Notch signaling leads to activation of parallel survival and apoptotic pathways in endothelial cells. The interaction of Notch with other signaling pathways plays an important contextual role in regulating endothelial viability.
内皮细胞活力的丧失与血管病理学的发生和进展相关。然而，对于维持细胞活力和细胞凋亡之间平衡所需的途径，我们仍有许多需要了解。Notch 的激活可以增强或抑制细胞凋亡，但它在维持内皮细胞方面的作用需要进一步阐明。
本研究旨在确定 Notch 激活调节内皮细胞活力的机制。
转导活性 Notch 的内皮细胞用脂多糖（LPS）或同型半胱氨酸处理，以诱导内皮细胞凋亡。Notch 可防止 LPS 诱导的细胞死亡，但加剧了同型半胱氨酸诱导的细胞凋亡。PI3K 抑制揭示了内源性 Notch 配体诱导的激活启动了平行的死亡和存活途径，并根据凋亡刺激对内皮细胞存活产生不同的影响。PI3K 活性调节 Slug 的表达，Slug 是 Notch 激活的内皮细胞中存活所必需的。同型半胱氨酸而不是 LPS，阻断了 Notch 激活细胞中的 PI3K 活性和 Slug 表达，导致内皮细胞凋亡增加。
Notch 信号在内皮细胞中导致平行的存活和凋亡途径的激活。Notch 与其他信号通路的相互作用在调节内皮细胞活力方面起着重要的背景作用。
