血管内皮生长因子(VEGF)及其受体(VEGFR)的失调与动脉粥样硬化和心血管疾病(CVD)使其成为心血管疾病风险评估的潜在目标。高通量筛选(HTS)方法已经产生了大规模的体外数据,提供有助于评估化学毒性和识别不良结局途径(AOPs)的分子起始事件(MIE)的机械信息.AOP代表了导致毒性的生物反应的逻辑顺序,并且是指导化学风险评估的有价值的工具。这里,我们使用HTS数据制定了一个AOP,该AOP将VEGF信号扰动与动脉粥样硬化相关.ToxCast,评估Tox21和PubChem数据以获得在靶向VEGFR的测定中有活性的4165种化合物的生物特征。化学信息学分析鉴定出109个丰富的结构指纹图谱。应用基于化学结构生物活性的子空间聚类方法产生了12个主要目标,AI辅助文献综述证实了其与CVD的相关性。通过将HTS数据突出的机械关系与文献综述结果相结合来假设AOP。连接血清素受体(HTR),雌激素受体α(ERα),和具有VEGFR活性的血管加压素受体(AVPR)靶标,血管生成信号,和动脉粥样硬化。几种内分泌干扰化学物质(EDCs),例如,双酚,三氯生,二氯二苯基三氯乙烷(DDT),和多氯联苯(PCBs),被确定为相关的化学应激源。这些化学物质的子空间聚类评估了潜在的MIE,并强调了与用例类的关联。通过将计算方法应用于分析HTS数据并假设机械AOP,这项研究提出了一种数据驱动的方法来评估环境心脏毒性,这最终可以补充和减少毒理学评估中动物试验的需要。
这项研究探讨了VEGFR的破坏如何导致动脉粥样硬化,动脉中斑块的积聚可导致CVD。通过分析与CV健康相关的HTS数据,研究人员确定了不同的化学物质如何影响VEGFR并可能导致CVD。使用这些筛选方法,快速测试许多化学物质,该研究确定了导致不良健康结果的特定生物学变化.这项研究旨在开发评估化学毒性的方法,而不依赖于动物试验,使其与人类健康相关。调查结果将某些化学品联系起来,例如,双酚和滴滴涕,改变VEGRF活性和动脉粥样硬化的发展。不良结果通路(AOP)框架将生物事件的序列从分子扰动映射到疾病,提供机械洞察力并识别影响AOP目标的化学物质。这种方法有助于了解环境化学品带来的风险,保护公众健康,同时减少动物实验。
Dysregulation of Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) contributes to atherosclerosis and cardiovascular disease (CVD), making it a potential target for CVD risk assessment. High throughput screening (HTS) approaches have resulted in large-scale in vitro data, providing mechanistic information that can help assess chemical toxicity and identify molecular-initiating events (MIEs) of adverse outcome pathways (AOPs). AOPs represent a logical sequence of biological responses contributing to toxicity and are valuable tools to inform chemical risk assessments. Here, we used HTS data to formulate an AOP relating VEGF signaling perturbation to atherosclerosis. ToxCast, Tox21, and PubChem data were evaluated to obtain bio-profiles of 4165 compounds active in assays targeting VEGFR. Cheminformatics analysis identified 109 enriched structural fingerprints. Applying a subspace clustering approach based on chemical structure bioactivity yielded 12 primary targets, whose relevance to CVD was confirmed by an AI-assisted literature review. An AOP was hypothesized by coupling mechanistic relationships highlighted by HTS data with literature review findings, linking Serotonin Receptor (HTR), Estrogen Receptor Alpha (ERα), and Vasopressin Receptor (AVPR) targets with VEGFR activity, angiogenic signaling, and atherosclerosis. Several endocrine disrupting chemicals (EDCs), e.g., bisphenols, triclosan, dichlorodiphenyltrichloroethane (DDT), and polychlorinated biphenyls (PCBs), were identified as relevant chemical stressors. Subspace clustering of these chemicals evaluated potential MIEs and highlighted associations with use-case classes. By applying computational methods to profile HTS data and hypothesize a mechanistic AOP, this study proposes a data-driven approach to evaluating environmental cardiotoxicity, which could eventually supplement and reduce the need for animal testing in toxicological assessments.
This study explores how disruptions in VEGFR contribute to atherosclerosis, the buildup of plaques in arteries that can lead to CVD. By analyzing data from HTS relevant to CV health, researchers identify how different chemicals affect VEGFR and potentially cause CVD. Using these screening methods, which quickly test many chemicals, the study identifies specific biological changes leading to adverse health outcomes. This research aims to develop methods to assess chemical toxicity without relying on animal testing, making it relevant to human health. The findings link certain chemicals e.g., bisphenols and DDT, changing VEGRF activity and the development of atherosclerosis. An adverse outcome pathway (AOP) framework maps the sequence of biological events from molecular perturbations to disease, providing mechanistic insight and identifying chemicals impacting the AOP targets. This approach helps understand the risks posed by environmental chemicals and protects public health while reducing animal experiments.