生物谷報道：威斯康星-邁迪遜大學(xué)（Wisconsin-Madison大學(xué)）醫(yī)學(xué)公共健康學(xué)院研究院最近發(fā)現(xiàn)一種控制血管新成的復(fù)雜機制,。Madison Paul P. Carbone 綜合性癌癥中心藥理學(xué)教授Emery Bresnick認為此發(fā)現(xiàn)有助于控制癌癥患者的腫瘤生長,。文章發(fā)表于9月25日JCB上,，是首次將神經(jīng)系統(tǒng)中的神經(jīng)肽與血管生長調(diào)控聯(lián)系起來,。
一般在傷口愈合,、例假,、懷孕或者胚胎發(fā)育等條件下會出現(xiàn)血管生長,，血管生長減弱和血管功能下降有可能導(dǎo)致失明,，腫瘤生長也離不開血管生長,。
如同許多關(guān)鍵生理過程一樣，血管新生（angiogenesis）受到許多機制的協(xié)調(diào)控制,。Bresnick和博士后Soumen Paul等開始進行研究時,，所關(guān)注的并不是血管新生，而是一種調(diào)節(jié)血細胞成熟的蛋白,，發(fā)現(xiàn)這種蛋白會打開編碼neurokinin-B（NK-B）的基因,。因為NK-B與神經(jīng)細胞有關(guān)，所以當時的發(fā)現(xiàn)令Bresnick驚愕：“為什么與血細胞形成有關(guān)的蛋白會開啟一種編碼有可能是控制神經(jīng)系統(tǒng)的蛋白的基因?”
研究人員開始尋找NK-B受體分子,，發(fā)現(xiàn)這些分子大量匯集于內(nèi)皮細胞（Endothelial cell）,。內(nèi)皮細胞構(gòu)成血管內(nèi)部結(jié)構(gòu),，在血管新生過程中通過遷移，使血管網(wǎng)絡(luò)不斷延長,。Paul向內(nèi)皮細胞加入NK-B,，“內(nèi)皮細胞失去了組織立體生長的功能，即失去了相互作用形成血管初級模型的功能,，”Bresnick說,，“我們感到非常振奮。”
接下來的工作中,，研究人員發(fā)現(xiàn)NK-B可以通過四種途徑抑制血管新生：抑制血管內(nèi)皮生長因子（vascular endothelial growth factor ,，VEGF）生成,VEGF是血管新生的關(guān)鍵刺激因子；降低VEGF受體數(shù)量,；減緩內(nèi)皮細胞的運動（此運動是形成新血管所必需的）,；提高一種剛剛發(fā)現(xiàn)的血管新生抑制因子的合成水平。Bresnick說：“雖然現(xiàn)在斷定NK-B是控制血管新生的總開關(guān)還為時尚早,，但迷人之處在于它能至少控制四種過程,，并且控制每個過程都能獨自抑制血管新生。”
Bresnick認為血管新生抑制劑是制藥領(lǐng)域的新大陸,。今年6月,，美國食品與藥品管理局（Food and Drug Administration, FDA ）首次核準一種可以恢復(fù)濕性（嚴重）老年黃斑病變(wet AMD)患者部分視力的血管新生抑制劑。wet AMD是由于視網(wǎng)膜下血管新生,，引致血管滲漏及出血引發(fā)的,，是引發(fā)老年患者失明的一大原因。
實體瘤的生長需要獲得新的血液供應(yīng),，成年人只有在懷孕和傷口愈合期才會出現(xiàn)血管新生,，因此阻斷血管新生應(yīng)該說是阻止腫瘤生長的希望,。同樣在今年6月,，F(xiàn)DA核準了一種能夠通過抑制VEGF治療結(jié)腸癌（colon cancer，美國第二大癌癥殺手）的新藥,，這種VEGF抑制劑可以降低血管新生,，最終使腫瘤饑餓而死。
調(diào)節(jié)血管新生是雙向的,，刺激血管新生有助于某些疾病的治療,。這項新的研究成果提示NK-B系統(tǒng)也能發(fā)揮刺激血管新生的功能。“激活NK-B受體即能阻斷血管新生,，抑制NK-B受體即能刺激血管新生”Bresnick說,。理論上，選擇性刺激血管新生可以通過促進心臟血管生長,，向受損心肌提高血供而治療心臟病,。
NK-B在一種神秘但又常見的疾病——驚厥（preeclampsia）中發(fā)揮重要作用,。驚厥發(fā)生時血壓升高、紅細胞攜氧能力下降,，嚴重時會導(dǎo)致孕婦和胎兒死亡,。英國雷丁大學(xué)（University of Reading）研究人員Philip Lowry發(fā)現(xiàn)，驚厥時NK-B水平急劇上升,。與新發(fā)現(xiàn)的NK-B在血管新生中的作用聯(lián)系起來,，似乎提示驚厥是由于血管新生發(fā)生缺陷引起的。
因為NK-B能夠抑制內(nèi)皮細胞組裝成血管,，Bresnick說：“驚厥中出現(xiàn)的NK-B過高表達,，也許是受損血管恢復(fù)功能所必需的。”
目前威斯康辛女校友研究基地（Wisconsin Alumni Research Foundation）已經(jīng)為新發(fā)現(xiàn)的控制NK-B翻譯的蛋白申請了專利,。Bresnick及其同事正在對NK-B進行人類細胞和小鼠模型實驗,。
研究人員相信NK-B終會在腫瘤等與血管新生有關(guān)的疾病治療中扮演重要角色。下一個關(guān)鍵問題是：我們怎樣開發(fā)NK-B的治療潛力,？
原始出處：
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."
Source-Newswise
SRM
