Need glucose to sprout: local metabolic control of angiogenesis.
Need glucose to sprout: local metabolic control of angiogenesis.
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DOI：
10.1002/emmm.201303174
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发表时间：
2013-10
影响因子：
11.1
通讯作者：
Simons, Michael
中科院分区：
文献类型：
--
作者：
Eichmann, Anne;Simons, Michael
血管生成研究的焦点主要集中在调节各种关键内皮细胞过程如迁移、增殖和毛细血管出芽的分子机制上。这导致了许多见解，包括VEGF信号传导在启动血管生成中发挥的关键作用（Chung &费拉拉，2011; Koch & Claesson‐Welsh，2012）和Notch信号传导通过控制这些过程调节其程度（Benedito & Hellstrom，2013; Cristofaro et al，2013;托马斯et al，2013）。这进一步发展成通过调节这些信号传导事件来控制血管生成的治疗方法，这些信号传导事件现在已被大量详细地了解。然而，迄今为止，很少有人关注血管生成的代谢成本。所有活跃的细胞活动，包括上面提到的活动，都需要消耗能量。基本的假设一直是能源（例如。ATP）是丰富的，并且不是限制因素，因为内皮细胞通常在血流的高氧环境中发现。事实上，虽然动脉内皮细胞沐浴在氧分压（PO 2）接近100 mmHg的血液中，但即使是静脉和淋巴管内皮细胞也暴露于比大多数其他组织高得多的PO 2（40 mmHg）。此外，基本上所有的体外生长因子信号传导的研究，使我们目前的VEGF和Notch生物学的理解，也已经在高氧环境中进行。然而，在许多情况下，血管生成是在低氧环境中启动的：考虑发育中的视网膜或肿瘤血管系统，其中尖端细胞（主要负责启动新毛细血管生长的内皮细胞亚群）很可能处于O2限制环境中。在这种背景下，De Bock et al（2013）最近的研究尤为及时和重要。作者表明，即使在高氧环境中，内皮细胞也通过糖酵解产生大部分能量，而不是通过氧化或脂肪酸代谢。此外，ATP在整个细胞中以这种方式产生，包括在片状伪足，这对毛细血管尖端细胞发芽至关重要。最后，能量的可用性本身是控制发芽的关键因素：足够的能量供应足以克服Notch信号传导的抑制作用，迄今为止，Notch信号传导被认为是控制该事件的主导信号传导机制。这些观察结果将内皮代谢的考虑推到了中心阶段。作者将注意力集中在糖酵解的最初关键步骤：果糖-6-磷酸转化为果糖-1，6-二磷酸。这是由限速酶磷酸果糖激酶-1（PFK 1）完成的。PFK 1的活性，反过来，由变构调节剂，果糖-2，6-二磷酸（Fru-2，6-BP）调节。后者也由另一种酶6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶-3（PFKFB 3）从果糖-6-磷酸产生，也称为磷酸果糖激酶-2（PFK 2）（图1A）。PFKFB 3是PFKFB家族中四种密切相关的蛋白质之一，并且是在内皮细胞中表达的主要同种型。有趣的是，该分子本身的表达受HIF-1a-（Obach et al，2004）和AMPK（门多萨et al，2012）调节，这是在能量限制情况下驱动内皮代谢的重要步骤。PFKFB 3的内皮缺失导致血管生成受损，其特征在于体外和体内内皮发芽减少。在镶嵌发芽试验中，PFKFB 3缺陷细胞的数量在尖端位置减少。在细胞水平上，板状伪足减少...
Much of the focus of research in angiogenesis has been on the molecular mechanisms regulating various critical endothelial cell processes such as migration, proliferation and capillary sprouting. This has led to a number of insights including the key roles played by VEGF signalling in initiating angiogenesis (Chung & Ferrara, 2011; Koch & Claesson‐Welsh, 2012) and Notch signalling in regulating its extent via control of these processes (Benedito & Hellstrom, 2013; Cristofaro et al, 2013; Thomas et al, 2013). This further evolved into therapeutic approaches designed to control angiogenesis by regulation of these signalling events that are now understood in a significant amount of detail. Yet little attention however has been paid so far to the metabolic cost of angiogenesis. All active cellular events, including the ones referred to above, require the expenditure of energy. The underlying assumption has always been that energy (eg. ATP) is abundant and is not a limiting factor as endothelial cells are typically found in the high oxygen environment of blood flow. Indeed, while arterial endothelium is bathed in blood with nearly 100mm Hg of partial pressure of oxygen (PO2), even venous and lymphatic endothelial cells are exposed to a much higher PO2 (40mmHg) than most other tissues. Furthermore, essentially all studies of growth factor signalling in vitro that have given us our current understanding of VEGF and Notch biology, have also been carried out in high oxygen environments. Yet in many instances angiogenesis is initiated in low oxygen‐environments: consider the developing retina or tumour vasculature where tip cells, an endothelial cell subset that largely is responsible for initiation of new capillary growth, may well be in O2‐limited environment. In this context, the recent study of De Bock et al (2013) is especially timely and important. The authors show that endothelial cells, even in a high oxygen environment, generate most of their energy via glycolysis and not via oxidative or fatty acid metabolism. Furthermore, ATP is generated in this fashion throughout the cell including at lamellipodia, which are crucial to capillary tip cell sprouting. Finally, the availability of energy is itself a key factor controlling sprouting: a sufficient supply of energy is enough to overcome the suppressive effect of Notch signalling that hitherto was considered to be the dominant signalling mechanism controlling this event. These observations propel considerations of endothelial metabolism to the centre stage. The authors concentrated their attention on the initial key step of glycolysis: conversion of fructose‐6‐phosphate to fructose‐1, 6‐biphosphate. This is accomplished by the rate‐limiting enzyme phosphofructokinase‐1 (PFK1). PFK1 activity, in turn, is modulated by an allosteric regulator, fructose‐2, 6‐bisphosphate (Fru‐2, 6‐BP). The latter is also produced from fructose‐6‐phosphate by another enzyme, 6‐phosphofructo‐2‐kinase/fructose‐2, 6‐bisphosphatase‐3 (PFKFB3) also known as phosphofructokinase‐2 (PFK2)(Fig 1A). PFKFB3 is one of four closely related proteins in the PFKFB family and is the predominant isoform expressed in endothelial cells. Interestingly, the expression of the molecule itself is regulated by HIF‐1a‐(Obach et al, 2004) and AMPK (Mendoza et al, 2012), an essential step in driving endothelial metabolism under energy‐limiting circumstances. Endothelial deletion of PFKFB3 resulted in impaired angiogenesis that was characterized by a reduction in endothelial sprouting in vitro and in vivo. In mosaic sprouting assays the number of PFKFB3‐deficient cells was reduced at the tip position. At the cellular level there was a decrease in lamellipodia …
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影响因子：
8.8
作者：
Chen PY;Qin L;Barnes C;Charisse K;Yi T;Zhang X;Ali R;Medina PP;Yu J;Slack FJ;Anderson DG;Kotelianski V;Wang F;Tellides G;Simons M
通讯作者：
Simons M
影响因子：
64.8
作者：
Hagberg, Carolina E.;Falkevall, Annelie;Eriksson, Ulf
通讯作者：
Eriksson, Ulf
影响因子：
5
作者：
Mendoza, Erin E.;Pocceschi, Michael G.;Burd, Randy
通讯作者：
Burd, Randy
影响因子：
64.5
作者：
De Bock, Katrien;Georgiadou, Maria;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
15.9
作者：
Murakami, Masahiro;Nguyen, Loc T.;Simons, Michael
通讯作者：
Simons, Michael