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The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects
Point of Contact
- Yanhong Wei
|Handbook Version||OECD status||OECD project|
This AOP was last modified on November 06, 2023 10:21
|Increase, Reactive Oxygen Species production||April 11, 2021 18:03|
|Increase, Oxidative Stress||March 03, 2022 10:40|
|Activation of inflammation pathway||May 31, 2022 02:47|
|Activated ANG/Tie2 pathway||August 21, 2023 04:09|
|Activation, Dll4-Notch pathway||August 20, 2023 07:18|
|Activated BMP/TGF-beta pathway||August 21, 2023 04:25|
|Activated Wnt/Frizzled pathway||August 21, 2023 04:26|
|KE4 : Uncoupling, eNOS||November 09, 2017 06:43|
|Activated AKT/ERK/PI3K pathway||August 21, 2023 04:27|
|Inhibition VEGF/VEGFR pathway||August 21, 2023 04:29|
|Increase, Mitochondrial Dysfunction||July 18, 2023 13:57|
|Vascular barrier disruption||August 21, 2023 04:48|
|Impaired Platelet Aggregation||August 21, 2023 04:54|
|Increase, Vascular disrupting effects||August 19, 2023 20:12|
|increased，Vascular endothelial dysfunction||September 01, 2021 20:37|
|Angiogenesis dysfunction||August 28, 2023 05:00|
|Increase, ROS production leads to Increase, Oxidative Stress||August 21, 2023 04:55|
|Increase, Oxidative Stress leads to Activation, inflammation pathway||August 19, 2023 20:13|
|Increase, Oxidative Stress leads to Activated ANG/Tie2 pathway||August 21, 2023 04:56|
|Increase, Oxidative Stress leads to Activation, Dll4-Notch pathway||August 21, 2023 04:56|
|Increase, Oxidative Stress leads to Activated BMP/TGF-beta pathway||August 21, 2023 04:57|
|Increase, Oxidative Stress leads to Activated Wnt/Frizzled pathway||August 21, 2023 04:57|
|Increase, Oxidative Stress leads to Uncoupling, eNOS||August 21, 2023 04:58|
|Increase, Oxidative Stress leads to Activated AKT/ERK/PI3K pathway||August 21, 2023 04:59|
|Increase, Oxidative Stress leads to Inhibition VEGF/VEGFR pathway||August 21, 2023 04:59|
|Increase, Oxidative Stress leads to Increase, Mt Dysfunction||March 07, 2022 11:41|
|Activation, inflammation pathway leads to increased，Vascular endothelial dysfunction||August 19, 2023 20:14|
|Activated ANG/Tie2 pathway leads to increased，Vascular endothelial dysfunction||August 21, 2023 07:33|
|Activation, Dll4-Notch pathway leads to increased，Vascular endothelial dysfunction||August 20, 2023 07:21|
|Activated BMP/TGF-beta pathway leads to increased，Vascular endothelial dysfunction||August 21, 2023 07:34|
|Activated Wnt/Frizzled pathway leads to increased，Vascular endothelial dysfunction||August 21, 2023 07:34|
|Uncoupling, eNOS leads to increased，Vascular endothelial dysfunction||August 21, 2023 07:35|
|Activated AKT/ERK/PI3K pathway leads to increased，Vascular endothelial dysfunction||August 21, 2023 07:35|
|Inhibition VEGF/VEGFR pathway leads to increased，Vascular endothelial dysfunction||August 21, 2023 07:36|
|Increase, Mt Dysfunction leads to increased，Vascular endothelial dysfunction||August 21, 2023 07:36|
|increased，Vascular endothelial dysfunction leads to Impaired Platelet Aggregation||August 21, 2023 05:15|
|Vascular barrier disruption leads to Increase, Vascular disrupting effects||August 21, 2023 07:38|
|Impaired Platelet Aggregation leads to Increase, Vascular disrupting effects||August 21, 2023 07:39|
|increased，Vascular endothelial dysfunction leads to Angiogenesis dysfunction||August 28, 2023 05:01|
|Angiogenesis dysfunction leads to Increase, Vascular disrupting effects||August 28, 2023 05:03|
|increased，Vascular endothelial dysfunction leads to Vascular barrier disruption||August 21, 2023 07:37|
BACKGROUND: CVDs are the leading cause of morbidity and mortality worldwide. Vascular network is an essential channel of the chemical’s ADME process and an important target of toxic effect. Elucidating the AOP of vascular disrupting effects has an essential implication for identifying the vascular toxicological mechanism and supporting regulatory decision making. Some chemicals have been proven to be potential vascular disrupting compounds (pVDCs) altering the expression, activity, or function of molecular signals regulating blood vessel development and remodeling, and the critical event involves ROS-mediated oxidative stress.
RELEVANCE and APPLICATION: Vascular disruption is a broad concept. The intended use of this AOP in a regulatory context is the predictive toxicology of vascular disrupting hazards, especially for integrating data from high-throughput screening (HTS) assays into cell agent-based models for predicting vascular toxicology. As part of an integrated assessment of toxicity, this AOP can identify useful information for assessing adverse outcomes relevant to risk assessment and efficient use of resources for validation through predictive models related to vascular toxicity. AOP-based computer models that simulate vascular development can usher-in new virtual screening techniques to predict what might happen to the vascular when exposed to chemicals across different dose-time-stage scenarios[1, 2].
AOP Development Strategy
This AOP focuses on the vascular disrupting effect via ROS-mediated oxidative stress.The postulated molecular initiating event (MIE) for this AOP, may be invoked by effects on ROS-mediated oxidative stress. Downstream key events (KE) include Oxidative stress, Inflammatory, Activated ANG/Tie2 pathway, Activated Dll4-Notch pathway, Activated BMP/TGF-beta pathway, Activated Wnt/Frizzled pathway, Uncoupling, eNOS, Activated AKT/ERK/PI3K pathway, Inhibited VEGF/VEGFR pathway, Mitochondrial dysfunction, Vascular endothelial dysfunction. KE relationships (KERs) lead to Endothelial dysfunction and Vascular barrier dysruption, Angiogenesis dysfunction, and Impaired Platelet Aggregation. The severity of adverse outcomes (vascular disrupting effects) would ultimately vary by anatomical region, organ system, and physiological state when an MIE is invoked. Furthermore, in order to elucidate the AOP of vascular disrupting effect better, the established AOPs are included.
Summary of the AOP
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
|Type||Event ID||Title||Short name|
|MIE||257||Increase, Reactive Oxygen Species production||Increase, ROS production|
|KE||1969||Increase, Oxidative Stress||Increase, Oxidative Stress|
|KE||2009||Activation of inflammation pathway||Activation, inflammation pathway|
|KE||2170||Activated ANG/Tie2 pathway||Activated ANG/Tie2 pathway|
|KE||2164||Activation, Dll4-Notch pathway||Activation, Dll4-Notch pathway|
|KE||2171||Activated BMP/TGF-beta pathway||Activated BMP/TGF-beta pathway|
|KE||2172||Activated Wnt/Frizzled pathway||Activated Wnt/Frizzled pathway|
|KE||932||KE4 : Uncoupling, eNOS||Uncoupling, eNOS|
|KE||2173||Activated AKT/ERK/PI3K pathway||Activated AKT/ERK/PI3K pathway|
|KE||2174||Inhibition VEGF/VEGFR pathway||Inhibition VEGF/VEGFR pathway|
|KE||1968||Increase, Mitochondrial Dysfunction||Increase, Mt Dysfunction|
|KE||2178||Vascular barrier disruption||Vascular barrier disruption|
|KE||2179||Impaired Platelet Aggregation||Impaired Platelet Aggregation|
|KE||1928||increased，Vascular endothelial dysfunction||increased，Vascular endothelial dysfunction|
|KE||2181||Angiogenesis dysfunction||Angiogenesis dysfunction|
|AO||2161||Increase, Vascular disrupting effects||Increase, Vascular disrupting effects|
Relationships Between Two Key Events (Including MIEs and AOs)
Life Stage Applicability
|All life stages||High|
Overall Assessment of the AOP
The biological plausibility of KERs is strong due to the available mechanistic evidence present in studies from a wide variety of taxa. Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with lab mice, cell lines, and zebrafish. Previous studies provided evidence such as antagonism, knock-outs or knock-ins to probe the necessity of MIE and KE. And many studies explored the dose concordance, incidence concordance, and temporal concordance of KERs. Furthermore, the AOP can be anticipated based on broader chemical-specific knowledge.
Domain of Applicability
- Life Stage Applicability
The AOPs are not life stage specific
- Taxonomic Applicability
3. Sex Applicability
Essentiality of the Key Events
The biological plausibility of KERs is strong due to the available mechanistic evidence present in studies from a wide variety of taxa. ROS-mediated oxidative stress causes a variety of cellular responses. There are some studies used a weight-of-evidence approach in analyzing TOXCAST data and proposed the putative AOP pathway from MIE Increased Reactive Oxygen Species to KE Oxidative Stress to KE Increase, Inflammation. Furthermore, The essentiality of KERs is strong due to a variety of evidence from different controlled experimental designs with controls. Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with lab mice, cell lines, and zebrafish. The empirical support of KERs is largely found in toxicological studies derived from reference chemicals with dose-response and temporal concordance assessed.
The QWOE approach is an analytical method that utilizes causality criteria to assess the evidence-supported postulated AOP. Firstly, the hypothesis of action was presented and the quantitative evaluation of evidence ranging from no evidence (0) to strong for each category (3, strong and −3, strong counter) utilizing the evolved MIEs, KEs, and KERs. Subsequently, a ranked importance-based numerical weight was assigned to Bradford Hill causal considerations, and the composite score and confidence score for MIEs, KEs, and entire AOP were evaluated. All in all, the evidences of biological plausibility, essentiality, empirical evidence of dose-response, incidence and temporal concordance, consistency (among different biological contexts), and analogy (consistency across structurally similar chemicals) are strong in this AOP.
Known Modulating Factors
|Modulating Factor (MF)||Influence or Outcome||KER(s) involved|
Optional field to provide quantitative weight of evidence descriptors.
Considerations for Potential Applications of the AOP (optional)
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