這張圖片顯示生長中的小鼠視網(wǎng)膜血管,。在沒有足夠氧氣供應(yīng)的情況下,，血管從組織的中心部分向外圍部分生長。圖片來自德國馬克斯-普朗克分子生物醫(yī)學(xué)研究所,。
Copyright ©版權(quán)Bioon.com所有,，若未得到生物谷授權(quán)，請勿轉(zhuǎn)載,。
血管新生(angiogenesis)是一種復(fù)雜的過程,，在這當(dāng)中不同的信號蛋白以一種高度協(xié)調(diào)的方式進行相互作用。生長因子VEGF 和Notch信號傳導(dǎo)途徑都在這種過程中發(fā)揮著重要的作用,。VEGF通過結(jié)合到它的受體VEGFR2上來促進血管生長,，而Notch信號傳導(dǎo)途徑發(fā)揮著類似開關(guān)那樣的作用，能夠抑制血管生長,。
直到現(xiàn)在,，科學(xué)家們一直假設(shè)Notch通過下調(diào)VEGFR2表達來取消VEGF發(fā)揮的作用。
不受控制的血管新生產(chǎn)生一些疾病,，如血管瘤(hemangioma)，即皮膚中血管海綿狀過度生長,，或者視網(wǎng)膜病,，它損害糖尿病病人和老年人的視力。
但是,，在癌癥治療中,，人們常用抑制VEGF或VEGFR2的方式來阻斷新血管的形成，從而阻止?fàn)I養(yǎng)物和氧氣通過血液循環(huán)輸送到癌細胞中,，從而將它們餓死并阻止它們通過血液循環(huán)進行轉(zhuǎn)移性擴散,。然而，不幸的是,，現(xiàn)存的治療方法并不充足：一些病人因為某些未知的原因?qū)EGF/VEGFR2抑制治療反應(yīng)較差或者根本就不產(chǎn)生反應(yīng),。
如今，來自德國馬克斯-普朗克分子生物醫(yī)學(xué)研究所(Max Planck Institute for Molecular Biomedicine)和明斯特大學(xué)(Westphalian Wilhelms-University of Münster)的研究人員證實在小鼠眼睛血管中,，抑制Notch途徑,，即便當(dāng)VEGF或VEGFR2受到抑制時，導(dǎo)致血管強勁地和不受控制地生長,。他們還發(fā)現(xiàn)一種不同的VEGF蛋白家族受體VEGFR3被極大地上調(diào),，從而促進血管生長。當(dāng)Notch缺失時,，VEGFR3在血管中也被極大地上調(diào),，而且即便來自周圍組織的生長信號不存在時，它也保持活性,。
這項發(fā)現(xiàn)可能有助于解釋在某些癌癥治療中產(chǎn)生的藥物抗性問題,，而且有可能為人們開發(fā)新的治療策略打下基礎(chǔ),。
接下來，研究人員需要證實VEGFR3和其他受Notch調(diào)控的信號確實能夠在小鼠和人類的眼睛疾病與癌癥中促進不依賴于VEGF的血管生長,。根據(jù)病人血管中Notch信號激活狀態(tài),，人們就可能預(yù)測VEGF或VEGFR2抑制治療是否對病人有效，從而可以允許醫(yī)生在必要時選擇替代治療手段,。(生物谷：towersimper編譯)
Copyright ©版權(quán)Bioon.com所有,，若未得到生物谷授權(quán)，請勿轉(zhuǎn)載,。
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.
