Biomechanical stimulation promotes blood vessel growth despite VEGFR-2 inhibition.
Biomechanical stimulation promotes blood vessel growth despite VEGFR-2 inhibition.
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DOI：
10.1186/s12915-023-01792-y
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发表时间：
2023-12-10
期刊：
影响因子：
5.4
通讯作者：
Sewell-Loftin, Mary Kathryn
中科院分区：
文献类型：
--
作者：
Johnson, Bronte Miller;Johnson, Allison McKenzie;Heim, Michael;Buckley, Molly;Mortimer, Bryan;Berry, Joel L.;Sewell-Loftin, Mary Kathryn
血管生成，或从现有血管生长新的脉管系统，被广泛认为是癌症进展的主要标志。当肿瘤很小时，扩散足以接收必需的营养物质;然而，随着肿瘤的生长，需要血管供应来将氧气和营养物质输送到不断增加的肿块中。几种抗血管生成癌症疗法靶向VEGF和受体VEGFR-2，它们是血管发育的主要促进剂。不幸的是，这些癌症治疗中的许多未能完全停止肿瘤微环境（TME）中的血管生成。由于这些疗法的重点是通过VEGF配体结合的VEGFR-2的生化激活，我们提出，机械线索，特别是那些在TME中发现的，可能是VEGFR-2激活的来源，即使在VEGF和VEGFR-2抑制剂的存在下，也能促进血管网络的生长。在本文中，我们分析了VEGFR-2的磷酸化模式，特别是在Y1054/Y1059和Y1214，通过VEGF或生物力学刺激的形式的拉伸应变刺激。我们的研究结果表明，延长和增强激活Y1054/Y1059和Y1214残基时，内皮细胞刺激应变，VEGF，或两者的组合。我们还分析了Src的表达，它是VEGFR-2的下游，可以通过应变或VEGF的存在被激活。最后，我们使用纤维蛋白凝胶和微流体装置作为三维微组织模型来模拟TME。我们确定，即使通过SU 5416抑制VEGFR-2，机械应变区域也促进血管生长增加。总体而言，了解生物力学和生物化学刺激对VEGFR-2活化和血管生成的影响是开发有效抗血管生成疗法的重要因素。这篇论文表明，VEGFR-2可以通过应变机械激活，这可能有助于增加TME中的血管生成。这些概念验证研究表明，当引入机械应变时，VEGFR-2的小分子抑制剂不能完全阻止3D TME模型中的血管生成。在线版本包含补充材料，可通过10.1186/s12915-023-01792-y获得。
Angiogenesis, or the growth of new vasculature from existing blood vessels, is widely considered a primary hallmark of cancer progression. When a tumor is small, diffusion is sufficient to receive essential nutrients; however, as the tumor grows, a vascular supply is needed to deliver oxygen and nutrients into the increasing mass. Several anti-angiogenic cancer therapies target VEGF and the receptor VEGFR-2, which are major promoters of blood vessel development. Unfortunately, many of these cancer treatments fail to completely stop angiogenesis in the tumor microenvironment (TME). Since these therapies focus on the biochemical activation of VEGFR-2 via VEGF ligand binding, we propose that mechanical cues, particularly those found in the TME, may be a source of VEGFR-2 activation that promotes growth of blood vessel networks even in the presence of VEGF and VEGFR-2 inhibitors. In this paper, we analyzed phosphorylation patterns of VEGFR-2, particularly at Y1054/Y1059 and Y1214, stimulated via either VEGF or biomechanical stimulation in the form of tensile strains. Our results show prolonged and enhanced activation at both Y1054/Y1059 and Y1214 residues when endothelial cells were stimulated with strain, VEGF, or a combination of both. We also analyzed Src expression, which is downstream of VEGFR-2 and can be activated through strain or the presence of VEGF. Finally, we used fibrin gels and microfluidic devices as 3D microtissue models to simulate the TME. We determined that regions of mechanical strain promoted increased vessel growth, even with VEGFR-2 inhibition through SU5416. Overall, understanding both the effects that biomechanical and biochemical stimuli have on VEGFR-2 activation and angiogenesis is an important factor in developing effective anti-angiogenic therapies. This paper shows that VEGFR-2 can be mechanically activated through strain, which likely contributes to increased angiogenesis in the TME. These proof-of-concept studies show that small molecular inhibitors of VEGFR-2 do not fully prevent angiogenesis in 3D TME models when mechanical strains are introduced. The online version contains supplementary material available at 10.1186/s12915-023-01792-y.
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影响因子：
4.8
作者：
Han, B;Bai, XH;Liu, MY
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分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
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