Division of Oncology, Department of Pediatric Surgery, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China.
Br J Dermatol. 2014 Jan;170(1):78-86. doi: 10.1111/bjd.12592.
The autocrine vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-2 loop is required to maintain the transformed phenotype of many tumours, in part, by preventing apoptotic cell death in response to many different stimuli. However, it is unclear whether constitutive VEGF/VEGFR-2 activation in haemangioma-derived endothelial cells (HaemECs) can lead to a general suppression of apoptosis.
The objective of this study was to investigate whether the autocrine VEGF loop promotes HaemEC survival via its receptor, VEGFR-2.
HaemECs and human umbilical vein endothelial cells (HUVECs) were serum-starved for 12-48 h. Cell apoptosis was measured. The potential mechanisms of VEGF/VEGFR-2-induced HaemEC survival were investigated, and the role of the autocrine VEGF/VEGFR-2 loop in preventing propranolol-induced apoptotic HaemEC death was also analysed.
Compared with HUVECs, HaemECs showed increased resistance to apoptosis induced by serum starvation. Upregulated VEGF/VEGFR-2 signalling in HaemECs induced an autocrine signalling loop, which resulted in Akt activation. Furthermore, this activation of Akt was necessary for VEGF/VEGFR-2-induced protection against serum deprivation-induced HaemEC apoptosis. In addition, Bcl-2, which functions as an anti-apoptotic factor and direct downstream target of PI3K/Akt, was decreased by the inhibition of VEGF/VEGFR-2, which led to an increase in caspase-3 activity, caspase-9 activity and HaemEC apoptosis. Moreover, HaemECs acquired greater resistance to propranolol treatment than HUVECs, whereas inhibition of VEGF/VEGFR-2 signalling in HaemECs sensitized these cells to propranolol-induced apoptosis.
Our results demonstrate that upregulation of the autocrine VEGF/VEGFR-2 loop can induce general resistance to apoptotic stimuli in HaemECs.
自分泌血管内皮生长因子 (VEGF)/VEGF 受体 (VEGFR)-2 环对于维持许多肿瘤的转化表型是必需的，部分原因是通过防止对许多不同刺激的凋亡细胞死亡。然而，尚不清楚血管生成性血管瘤衍生的内皮细胞 (HaemECs) 中的组成性 VEGF/VEGFR-2 激活是否会导致普遍抑制细胞凋亡。
本研究旨在探讨自分泌 VEGF 环是否通过其受体 VEGFR-2 促进 HaemEC 存活。
将 HaemECs 和人脐静脉内皮细胞 (HUVECs) 饥饿血清 12-48 小时。测量细胞凋亡。研究了 VEGF/VEGFR-2 诱导 HaemEC 存活的潜在机制，并分析了自分泌 VEGF/VEGFR-2 环在防止普萘洛尔诱导的凋亡 HaemEC 死亡中的作用。
与 HUVECs 相比，HaemECs 对血清饥饿诱导的凋亡表现出更高的抵抗力。HaemECs 中上调的 VEGF/VEGFR-2 信号诱导了一个自分泌信号环，导致 Akt 激活。此外，VEGF/VEGFR-2 诱导的 Akt 激活对于防止血清剥夺诱导的 HaemEC 凋亡是必需的。此外，作为抗凋亡因子和 PI3K/Akt 的直接下游靶标的 Bcl-2 被 VEGF/VEGFR-2 抑制下调，导致 caspase-3 活性、caspase-9 活性和 HaemEC 凋亡增加。此外，HaemECs 对普萘洛尔治疗的抵抗力比 HUVECs 更强，而 HaemECs 中 VEGF/VEGFR-2 信号的抑制使这些细胞对普萘洛尔诱导的凋亡敏感。
我们的研究结果表明，自分泌 VEGF/VEGFR-2 环的上调可以诱导 HaemEC 对凋亡刺激的普遍抵抗力。
