生物谷报道:威斯康星-迈迪逊大学(Wisconsin-Madison大学)医学公共健康学院研究院最近发现一种控制血管新成的复杂机制。Madison Paul P. Carbone 综合性癌症中心药理学教授Emery Bresnick认为此发现有助于控制癌症患者的肿瘤生长。文章发表于9月25日JCB上,是首次将神经系统中的神经肽与血管生长调控联系起来。
一般在伤口愈合、例假、怀孕或者胚胎发育等条件下会出现血管生长,血管生长减弱和血管功能下降有可能导致失明,肿瘤生长也离不开血管生长。
如同许多关键生理过程一样,血管新生(angiogenesis)受到许多机制的协调控制。Bresnick和博士后Soumen Paul等开始进行研究时,所关注的并不是血管新生,而是一种调节血细胞成熟的蛋白,发现这种蛋白会打开编码neurokinin-B(NK-B)的基因。因为NK-B与神经细胞有关,所以当时的发现令Bresnick惊愕:“为什么与血细胞形成有关的蛋白会开启一种编码有可能是控制神经系统的蛋白的基因?”
研究人员开始寻找NK-B受体分子,发现这些分子大量汇集于内皮细胞(Endothelial cell)。内皮细胞构成血管内部结构,在血管新生过程中通过迁移,使血管网络不断延长。Paul向内皮细胞加入NK-B,“内皮细胞失去了组织立体生长的功能,即失去了相互作用形成血管初级模型的功能,”Bresnick说,“我们感到非常振奋。”
接下来的工作中,研究人员发现NK-B可以通过四种途径抑制血管新生:抑制血管内皮生长因子(vascular endothelial growth factor ,VEGF)生成,VEGF是血管新生的关键刺激因子;降低VEGF受体数量;减缓内皮细胞的运动(此运动是形成新血管所必需的);提高一种刚刚发现的血管新生抑制因子的合成水平。Bresnick说:“虽然现在断定NK-B是控制血管新生的总开关还为时尚早,但迷人之处在于它能至少控制四种过程,并且控制每个过程都能独自抑制血管新生。”
Bresnick认为血管新生抑制剂是制药领域的新大陆。今年6月,美国食品与药品管理局(Food and Drug Administration, FDA )首次核准一种可以恢复湿性(严重)老年黄斑病变(wet AMD)患者部分视力的血管新生抑制剂。wet AMD是由于视网膜下血管新生,引致血管渗漏及出血引发的,是引发老年患者失明的一大原因。
实体瘤的生长需要获得新的血液供应,成年人只有在怀孕和伤口愈合期才会出现血管新生,因此阻断血管新生应该说是阻止肿瘤生长的希望。同样在今年6月,FDA核准了一种能够通过抑制VEGF治疗结肠癌(colon cancer,美国第二大癌症杀手)的新药,这种VEGF抑制剂可以降低血管新生,最终使肿瘤饥饿而死。
调节血管新生是双向的,刺激血管新生有助于某些疾病的治疗。这项新的研究成果提示NK-B系统也能发挥刺激血管新生的功能。“激活NK-B受体即能阻断血管新生,抑制NK-B受体即能刺激血管新生”Bresnick说。理论上,选择性刺激血管新生可以通过促进心脏血管生长,向受损心肌提高血供而治疗心脏病。
NK-B在一种神秘但又常见的疾病——惊厥(preeclampsia)中发挥重要作用。惊厥发生时血压升高、红细胞携氧能力下降,严重时会导致孕妇和胎儿死亡。英国雷丁大学(University of Reading)研究人员Philip Lowry发现,惊厥时NK-B水平急剧上升。与新发现的NK-B在血管新生中的作用联系起来,似乎提示惊厥是由于血管新生发生缺陷引起的。
因为NK-B能够抑制内皮细胞组装成血管,Bresnick说:“惊厥中出现的NK-B过高表达,也许是受损血管恢复功能所必需的。”
目前威斯康辛女校友研究基地(Wisconsin Alumni Research Foundation)已经为新发现的控制NK-B翻译的蛋白申请了专利。Bresnick及其同事正在对NK-B进行人类细胞和小鼠模型实验。
研究人员相信NK-B终会在肿瘤等与血管新生有关的疾病治疗中扮演重要角色。下一个关键问题是:我们怎样开发NK-B的治疗潜力?
原始出处:
An antiangiogenic neurokinin-B/thromboxane A2 regulatory axis
Saumen Pal, Jing Wu, Justin K. Murray, Samuel H. Gellman, Michele A. Wozniak, Patricia J. Keely, Meghan E. Boyer, Timothy M. Gomez, Sean M. Hasso, John F. Fallon, and Emery H. Bresnick
J. Cell Biol. 2006 174: 1047-1058. Published Sep 25 2006, 10.1083/jcb.200603152. [Abstract] [Full Text] [PDF] [Supplemental Material Index]
A researcher at the University of Wisconsin-Madison School of Medicine and Public Health has discovered a new part of the complicated mechanism that governs the formation of blood vessels, or angiogenesis.
The finding may help halt tumor growth in cancer patients, says Emery Bresnick, the senior author on the study, a professor of pharmacology and member of the UW-Madison Paul P. Carbone Comprehensive Cancer Center.
The research, published in the Journal of Cell Biology on Sept. 25, is the first to connect a particular nervous-system chemical to the regulation of blood vessels.
Normally, blood vessels form when wounds heal and during menstruation, pregnancy and fetal development. But impaired blood-vessel development and function are also a major cause of blindness, and tumors rely on new blood vessels as they develop.
Like most critical body processes, angiogenesis is tightly controlled by multiple balancing mechanisms. When Bresnick and colleagues, including postdoctoral fellow Soumen Paul, began the new study, they were not looking into angiogenesis. Instead, they were studying a protein that regulates the maturation of blood cells, and noticed that it turns on a gene that makes a compound called neurokinin-B, or NK-B.
Aware that NK-B affects cells in the nervous system, Bresnick wondered, 'Why would a protein involved in blood-cell formation turn on the gene for a compound that is supposedly involved in regulating the nervous system?'
The researchers searched for NK-B receptors - molecules that can 'recognize' and respond to NK-B - and found great numbers of them on endothelial cells, which line the inside of blood vessels.
Endothelial cells form the internal structure of a blood vessel, and during angiogenesis, they migrate, starting an extension of the blood-vessel network. When Paul added NK-B to endothelial cells, "They lost the capacity to organize in three dimensions, to form the tubes that are the precursors to new blood vessels," Bresnick says. "Then we got excited."
Further tests showed that NK-B could inhibit angiogenesis in four ways. It prevents the production of vascular endothelial growth factor (VEGF), a key stimulator of blood-vessel formation, and also reduces the number of receptor molecules that respond to VEGF. NK-B also slows the movement of endothelial cells, which is necessary to form new vessels, and raises the level of a newly discovered angiogenesis inhibitor.
"It's premature to call it a master switch, but intriguingly, it regulates at least four different processes, each of which individually would be anti-angiogenic," says Bresnick.
Angiogenesis inhibitors, Bresnick observes, are a fast-growing field of medicine. This June, the Food and Drug Administration approved an angiogenesis inhibitor as the first drug that can restore some vision in the more severe ("wet") form of age-related macular degeneration (AMD). Wet AMD occurs when leaky blood vessels form in the retina. Along with a similar growth of new blood vessels in diabetes, it is the major cause of blindness in older adults.
But the "holy grail" of angiogenesis inhibition concerns cancer treatment. Before solid tumors start to grow, they must create a new blood supply, and since adults need angiogenesis only during pregnancy and to heal wounds, blocking angiogenesis could be a promising way to halt tumor growth. Also in June, the FDA approved a compound that inhibits VEGF for treating colon cancer, the second-leading cause of cancer death in the United States. The VEGF-inhibitor reduces the formation of blood vessels, helping starve tumors.
But angiogenesis regulation is a two-way street, and there are some diseases in which it might be desirable to stimulate angiogenesis. The new research shows that the NK-B system can work both ways: Reducing inhibition seems to increase angiogenesis.
"Activating the NK-B receptor blocked angiogenesis, and blocking the receptor stimulated angiogenesis," Bresnick says. In theory, selectively stimulating angiogenesis could help treat heart attacks by restoring blood flow to the heart, increasing the blood supply to threatened heart muscle.
NK-B also plays a role in a mysterious but common syndrome called preeclampsia, in which soaring blood pressure and low blood oxygen levels harm or even kill pregnant women and their babies. Philip Lowry, at the University of Reading in the United Kingdom, has found that NK-B levels spike in preeclampsia, and the new understanding of NK-B's role in angiogenesis suggests that faulty blood-vessel formation may be to blame.
Because NK-B prevents endothelial cells from organizing into blood vessels, Bresnick says, "Maybe excess levels of NK-B are responsible for or contribute to impaired vascular development/function and certain symptoms of preeclampsia." According to the Preeclampsia Foundation, the condition affects about 200,000 American women each year.
Many angiogenesis inhibitors are under study at this point, but finding a regulatory molecule that affects four separate mechanisms "makes for an interesting package," Bresnick says.
The Wisconsin Alumni Research Foundation has applied for a patent on the discovery, which, says Bresnick, reflected the work of "outstanding collaborators at the University of Wisconsin-Madison, who facilitated this multidisciplinary study and co-authored this paper." Authors included Patricia Keely in the Department of Pharmacology; John Fallon and Tim Gomez in the Department of Anatomy; and Sam Gellman in the Department of Chemistry.
Bresnick and his collaborators are looking further into how the molecule works in human cells and in mouse models of angiogenesis.
Eventually, after years of basic research and drug development, the multitalented compound NK-B could wind up playing a major role in treating cancer and other diseases where blood vessel formation goes awry, Bresnick says. "We have discovered a new peptide that clearly suppresses angiogenesis via a novel multi-component mechanism," he says. "A key question is whether we can exploit it to develop therapeutics."
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