这张图片显示生长中的小鼠视网膜血管。在没有足够氧气供应的情况下，血管从组织的中心部分向外围部分生长。图片来自德国马克斯-普朗克分子生物医学研究所。
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血管新生(angiogenesis)是一种复杂的过程，在这当中不同的信号蛋白以一种高度协调的方式进行相互作用。生长因子VEGF 和Notch信号传导途径都在这种过程中发挥着重要的作用。VEGF通过结合到它的受体VEGFR2上来促进血管生长，而Notch信号传导途径发挥着类似开关那样的作用，能够抑制血管生长。
直到现在，科学家们一直假设Notch通过下调VEGFR2表达来取消VEGF发挥的作用。
不受控制的血管新生产生一些疾病，如血管瘤(hemangioma)，即皮肤中血管海绵状过度生长，或者视网膜病，它损害糖尿病病人和老年人的视力。
但是，在癌症治疗中，人们常用抑制VEGF或VEGFR2的方式来阻断新血管的形成，从而阻止营养物和氧气通过血液循环输送到癌细胞中，从而将它们饿死并阻止它们通过血液循环进行转移性扩散。然而，不幸的是，现存的治疗方法并不充足：一些病人因为某些未知的原因对VEGF/VEGFR2抑制治疗反应较差或者根本就不产生反应。
如今，来自德国马克斯-普朗克分子生物医学研究所(Max Planck Institute for Molecular Biomedicine)和明斯特大学(Westphalian Wilhelms-University of Münster)的研究人员证实在小鼠眼睛血管中，抑制Notch途径，即便当VEGF或VEGFR2受到抑制时，导致血管强劲地和不受控制地生长。他们还发现一种不同的VEGF蛋白家族受体VEGFR3被极大地上调，从而促进血管生长。当Notch缺失时，VEGFR3在血管中也被极大地上调，而且即便来自周围组织的生长信号不存在时，它也保持活性。
这项发现可能有助于解释在某些癌症治疗中产生的药物抗性问题，而且有可能为人们开发新的治疗策略打下基础。
接下来，研究人员需要证实VEGFR3和其他受Notch调控的信号确实能够在小鼠和人类的眼睛疾病与癌症中促进不依赖于VEGF的血管生长。根据病人血管中Notch信号激活状态，人们就可能预测VEGF或VEGFR2抑制治疗是否对病人有效，从而可以允许医生在必要时选择替代治疗手段。(生物谷：towersimper编译)
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doi:10.1038/nature10908
PMC:
PMID:
Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF–VEGFR2 signalling
Rui Benedito, Susana F. Rocha, Marina Woeste, Martin Zamykal, Freddy Radtke, Oriol Casanovas, Antonio Duarte, Bronislaw Pytowski & Ralf H. Adams
Developing tissues and growing tumours produce vascular endothelial growth factors (VEGFs), leading to the activation of the corresponding receptors in endothelial cells. The resultant angiogenic expansion of the local vasculature can promote physiological and pathological growth processes. Previous work has uncovered that the VEGF and Notch pathways are tightly linked. Signalling triggered by VEGF-A (also known as VEGF) has been shown to induce expression of the Notch ligand DLL4 in angiogenic vessels and, most prominently, in the tip of endothelial sprouts. DLL4 activates Notch in adjacent cells, which suppresses the expression of VEGF receptors and thereby restrains endothelial sprouting and proliferation. Here we show, by using inducible loss-of-function genetics in combination with inhibitors in vivo, that DLL4 protein expression in retinal tip cells is only weakly modulated by VEGFR2 signalling. Surprisingly, Notch inhibition also had no significant impact on VEGFR2 expression and induced deregulated endothelial sprouting and proliferation even in the absence of VEGFR2, which is the most important VEGF-A receptor and is considered to be indispensable for these processes. By contrast, VEGFR3, the main receptor for VEGF-C, was strongly modulated by Notch. VEGFR3 kinase-activity inhibitors but not ligand-blocking antibodies suppressed the sprouting of endothelial cells that had low Notch signalling activity. Our results establish that VEGFR2 and VEGFR3 are regulated in a highly differential manner by Notch. We propose that successful anti-angiogenic targeting of these receptors and their ligands will strongly depend on the status of endothelial Notch signalling.
