A pro-angiogenic and hypoxic zebrafish model as a novel platform for anti-angiogenic drug testing.

IF 1.7 4区 生物学 Q3 BIOLOGY
Biology Open Pub Date : 2025-08-15 Epub Date: 2025-08-11 DOI:10.1242/bio.061863
Vinoth S, Kirankumar Santhakumar
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引用次数: 0

Abstract

Zebrafish is a valuable model for antiangiogenic drug testing. We hypothesized that the efficacy of antiangiogenic compounds might vary in hypoxic tissue environments compared to normal tissue. To explore this, we established a chemically induced zebrafish model using DMOG, which inhibits prolyl hydroxylases, and a genetic model by knocking out vhl gene via CRISPR/Cas9 to activate hypoxia signaling. In wild-type larvae, the antiangiogenic drug sorafenib inhibited blood vessel growth. However, in the DMOG model and vhl-/- model, no inhibition occurred in sub-intestinal vessel (SIV) upon sorafenib treatment. Also, gene expression analysis showed that the DMOG induced hypoxia had 20-fold increase in phd3 expression, a marker for hypoxia signaling activation, which rose to 65-fold and 280-fold with sorafenib treatment at the concentration 0.1 μM and 0.2 μM, respectively. In the vhl-/- model phd3 expression was found to be increased to 220-fold and reaching up to 400-fold with sorafenib treatment. This increased activation of hypoxia signaling elevated the proangiogenic factors like vegfaa, vegfab and vegfd, which might have protected the SIV region from sorafenib treatment in hypoxic models. This confirms that the hypoxia zebrafish models gained resistance against chemotherapeutic drugs by increasing the cellular hypoxia levels. Thus, our zebrafish model for hypoxia provides evidence that the efficacy of chemotherapy for cancer significantly depends on hypoxic microenvironment.

促血管生成和缺氧斑马鱼模型作为抗血管生成药物测试的新平台。
斑马鱼是一种有价值的抗血管生成药物试验模型。我们假设,与正常组织相比,抗血管生成化合物在缺氧组织环境中的功效可能有所不同。为此,我们利用DMOG抑制脯氨酰羟化酶建立了化学诱导斑马鱼模型,并通过CRISPR/Cas9敲除vhl基因激活缺氧信号的遗传模型。在野生型幼虫中,抗血管生成药物索拉非尼抑制血管生长。然而,在DMOG模型和vhl-/-模型中,索拉非尼治疗对亚肠血管(SIV)没有抑制作用。此外,基因表达分析显示,DMOG诱导的缺氧使缺氧信号激活标志物phd3的表达增加了20倍,在0.1 μM和0.2 μM浓度的索拉非尼处理下分别增加了65倍和280倍。在vhl-/-模型中,发现索拉非尼治疗后phd3的表达增加到220倍,最高可达400倍。这种缺氧信号激活的增加提高了促血管生成因子,如vegfaa, vegfab和vegfd,这可能在缺氧模型中保护SIV区域免受索拉非尼治疗的影响。这证实了缺氧斑马鱼模型通过增加细胞缺氧水平获得对化疗药物的耐药性。因此,我们的斑马鱼缺氧模型提供了证据,证明癌症化疗的疗效在很大程度上取决于缺氧微环境。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biology Open
Biology Open BIOLOGY-
CiteScore
3.90
自引率
0.00%
发文量
162
审稿时长
8 weeks
期刊介绍: Biology Open (BiO) is an online Open Access journal that publishes peer-reviewed original research across all aspects of the biological sciences. BiO aims to provide rapid publication for scientifically sound observations and valid conclusions, without a requirement for perceived impact.
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