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The authors have designated this AOP as all rights reserved. Re-use in any form requires advanced permission from the authors.

AOP: 511

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
The AOP framework on ROS-mediated oxidative stress induced vascular disrupting effects
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.6

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Yanhong Wei1, Jiayin Dai2, Jianshe Wang3

1 Sun Yat-sen University, Guangzhou, 510080, China.

2 Shanghai Jiao Tong University, Shanghai 200240, China

3 Yantai University, Yantai, 264005, China.

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Evgeniia Kazymova   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Yanhong Wei
  • Evgeniia Kazymova

Coaches

This field is used to identify coaches who supported the development of the AOP.Each coach selected must be a registered author. More help

OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on May 26, 2024 20:40

Revision dates for related pages

Page Revision Date/Time
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
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 June 19, 2024 19:48
Angiogenesis dysfunction August 28, 2023 05:00
Mitochondrial dysfunction April 17, 2024 08:26
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 Mitochondrial dysfunction February 21, 2024 15:47
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
Mitochondrial dysfunction leads to increased，Vascular endothelial dysfunction February 21, 2024 15:40
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

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

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.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
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 177 Mitochondrial dysfunction Mitochondrial 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)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help
Title Adjacency Evidence Quantitative Understanding
Increase, ROS production leads to Increase, Oxidative Stress adjacent High High
Increase, Oxidative Stress leads to Activation, inflammation pathway adjacent High High
Increase, Oxidative Stress leads to Activated ANG/Tie2 pathway adjacent Moderate Moderate
Increase, Oxidative Stress leads to Activation, Dll4-Notch pathway adjacent High High
Increase, Oxidative Stress leads to Activated BMP/TGF-beta pathway adjacent Low Low
Increase, Oxidative Stress leads to Activated Wnt/Frizzled pathway adjacent Low Low
Increase, Oxidative Stress leads to Uncoupling, eNOS adjacent High High
Increase, Oxidative Stress leads to Activated AKT/ERK/PI3K pathway adjacent Moderate Moderate
Increase, Oxidative Stress leads to Inhibition VEGF/VEGFR pathway adjacent High High
Increase, Oxidative Stress leads to Mitochondrial dysfunction adjacent High High
Activation, inflammation pathway leads to increased，Vascular endothelial dysfunction adjacent High High
Activated ANG/Tie2 pathway leads to increased，Vascular endothelial dysfunction adjacent High High
Activation, Dll4-Notch pathway leads to increased，Vascular endothelial dysfunction adjacent High High
Activated BMP/TGF-beta pathway leads to increased，Vascular endothelial dysfunction adjacent High High
Activated Wnt/Frizzled pathway leads to increased，Vascular endothelial dysfunction adjacent High High
Uncoupling, eNOS leads to increased，Vascular endothelial dysfunction adjacent High High
Activated AKT/ERK/PI3K pathway leads to increased，Vascular endothelial dysfunction adjacent High High
Inhibition VEGF/VEGFR pathway leads to increased，Vascular endothelial dysfunction adjacent High High
Mitochondrial dysfunction leads to increased，Vascular endothelial dysfunction adjacent High High
increased，Vascular endothelial dysfunction leads to Impaired Platelet Aggregation adjacent High High
Vascular barrier disruption leads to Increase, Vascular disrupting effects adjacent High High
Impaired Platelet Aggregation leads to Increase, Vascular disrupting effects adjacent High High
increased，Vascular endothelial dysfunction leads to Angiogenesis dysfunction adjacent High High
Angiogenesis dysfunction leads to Increase, Vascular disrupting effects adjacent High High
increased，Vascular endothelial dysfunction leads to Vascular barrier disruption adjacent High High

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
zebrafish Danio rerio High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

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

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help
  1. Life Stage Applicability

The AOPs are not life stage specific

  1. Taxonomic Applicability

Term

Scientific Term

Evidence

Link

Human

Homo sapiens

High

https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606

Mouse

Mus musculus

High

https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090

Zebrafish

Danio rerio

High

https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=7955

3. Sex Applicability

Mixed

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

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.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

The QWOE approach is an analytical method that utilizes causality criteria to assess the evidence-supported postulated AOP[4]. 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 factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved
     

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

Optional field to provide quantitative weight of evidence descriptors.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help

[1]        ELLIS-HUTCHINGS R G, SETTIVARI R S, MCCOY A T, et al. Embryonic vascular disruption adverse outcomes: Linking high throughput signaling signatures with functional consequences [J]. Reproductive toxicology (Elmsford, NY), 2017, 70: 82-96.

[2]        KLEINSTREUER N C, JUDSON R S, REIF D M, et al. Environmental impact on vascular development predicted by high-throughput screening [J]. Environ Health Perspect, 2011, 119(11): 1596-603.

[3]        LIND L, ARAUJO J A, BARCHOWSKY A, et al. Key Characteristics of Cardiovascular Toxicants [J]. Environ Health Perspect, 2021, 129(9): 95001.

[4]        BECKER R A, DELLARCO V, SEED J, et al. Quantitative weight of evidence to assess confidence in potential modes of action [J]. Regulatory toxicology and pharmacology : RTP, 2017, 86: 205-20.

[5]        HE F, RU X, WEN T. NRF2, a Transcription Factor for Stress Response and Beyond [J]. International journal of molecular sciences, 2020, 21(13).

[6]        KIM Y W, BYZOVA T V. Oxidative stress in angiogenesis and vascular disease [J]. Blood, 2014, 123(5): 625-31.

[7]        REY S, SEMENZA G L. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling [J]. Cardiovascular research, 2010, 86(2): 236-42.

[8]        KIRKMAN D L, ROBINSON A T, ROSSMAN M J, et al. Mitochondrial contributions to vascular endothelial dysfunction, arterial stiffness, and cardiovascular diseases [J]. American journal of physiology Heart and circulatory physiology, 2021, 320(5): H2080-h100.

[9]        FAGIANI E, CHRISTOFORI G. Angiopoietins in angiogenesis [J]. Cancer letters, 2013, 328(1): 18-26.

[10]       COSENTINO F, LüSCHER T F. Maintenance of vascular integrity: role of nitric oxide and other bradykinin mediators [J]. European heart journal, 1995, 16 Suppl K: 4-12.

[11]       ZHOU W, LIU K, ZENG L, et al. Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension [J]. Circulation, 2022, 146(24): 1855-81.

[12]       MORELLO F, PERINO A, HIRSCH E. Phosphoinositide 3-kinase signalling in the vascular system [J]. Cardiovascular research, 2009, 82(2): 261-71.

[13]       LOBOV I B, CHEUNG E, WUDALI R, et al. The Dll4/Notch pathway controls postangiogenic blood vessel remodeling and regression by modulating vasoconstriction and blood flow [J]. Blood, 2011, 117(24): 6728-37.

[14]       WEI Y, GONG J, XU Z, et al. Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A [J]. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(50): E6927-36.

[15]       SEGARRA M, OHNUKI H, MARIC D, et al. Semaphorin 6A regulates angiogenesis by modulating VEGF signaling [J]. Blood, 2012, 120(19): 4104-15.

[16]       DEANFIELD J E, HALCOX J P, RABELINK T J. Endothelial function and dysfunction: testing and clinical relevance [J]. Circulation, 2007, 115(10): 1285-95.

[17]       GODO S, SHIMOKAWA H. Endothelial Functions [J]. Arteriosclerosis, thrombosis, and vascular biology, 2017, 37(9): e108-e14.

[18]       INCALZA M A, D'ORIA R, NATALICCHIO A, et al. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases [J]. Vascul Pharmacol, 2018, 100: 1-19.

[19]       WEI Y, GONG J, XU Z, et al. Nrf2 promotes reparative angiogenesis through regulation of NADPH oxidase-2 in oxygen-induced retinopathy [J]. Free radical biology & medicine, 2016, 99: 234-43.

[20]       KIM Y W, WEST X Z, BYZOVA T V. Inflammation and oxidative stress in angiogenesis and vascular disease [J]. Journal of molecular medicine (Berlin, Germany), 2013, 91(3): 323-8.

[21]       REDZA-DUTORDOIR M, AVERILL-BATES D A. Activation of apoptosis signalling pathways by reactive oxygen species [J]. Biochimica et biophysica acta, 2016, 1863(12): 2977-92.

[22]       FERRI K F, KROEMER G. Organelle-specific initiation of cell death pathways [J]. Nature cell biology, 2001, 3(11): E255-63.

[23]       JIN Z, EL-DEIRY W S. Overview of cell death signaling pathways [J]. Cancer biology & therapy, 2005, 4(2): 139-63.

[24]       ZHONG X, QIU J, KANG J, et al. Exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) induces vascular toxicity through Nrf2-VEGF pathway in zebrafish and human umbilical vein endothelial cells [J]. Environmental pollution (Barking, Essex : 1987), 2019, 247: 293-301.

[25]       WEI Y, GONG J, THIMMULAPPA R K, et al. Nrf2 acts cell-autonomously in endothelium to regulate tip cell formation and vascular branching [J]. Proceedings of the National Academy of Sciences of the United States of America, 2013, 110(41): E3910-8.

[26]       XU Z, WEI Y, GONG J, et al. NRF2 plays a protective role in diabetic retinopathy in mice [J]. Diabetologia, 2014, 57(1): 204-13.

[27]       WEI Y, GONG J, YOSHIDA T, et al. Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury [J]. Free radical biology & medicine, 2011, 51(1): 216-24.

[28]       CIMINO F, SPECIALE A, ANWAR S, et al. Anthocyanins protect human endothelial cells from mild hyperoxia damage through modulation of Nrf2 pathway [J]. Genes & nutrition, 2013, 8(4): 391-9.

[29]       CHEN B, LU Y, CHEN Y, et al. The role of Nrf2 in oxidative stress-induced endothelial injuries [J]. The Journal of endocrinology, 2015, 225(3): R83-99.

[30]       ISHIKADO A, SONO Y, MATSUMOTO M, et al. Willow bark extract increases antioxidant enzymes and reduces oxidative stress through activation of Nrf2 in vascular endothelial cells and Caenorhabditis elegans [J]. Free radical biology & medicine, 2013, 65: 1506-15.

[31]       HAN S G, HAN S S, TOBOREK M, et al. EGCG protects endothelial cells against PCB 126-induced inflammation through inhibition of AhR and induction of Nrf2-regulated genes [J]. Toxicol Appl Pharmacol, 2012, 261(2): 181-8.

[32]       ZHANG J, FUKUHARA S, SAKO K, et al. Angiopoietin-1/Tie2 signal augments basal Notch signal controlling vascular quiescence by inducing delta-like 4 expression through AKT-mediated activation of beta-catenin [J]. The Journal of biological chemistry, 2011, 286(10): 8055-66.

[33]       ORRENIUS S, GOGVADZE V, ZHIVOTOVSKY B. Calcium and mitochondria in the regulation of cell death [J]. Biochemical and biophysical research communications, 2015, 460(1): 72-81.

[34]       ZHANG X, ZHENG C, GAO Z, et al. PKM2 promotes angiotensin-II-induced cardiac remodelling by activating TGF-β/Smad2/3 and Jak2/Stat3 pathways through oxidative stress [J]. Journal of cellular and molecular medicine, 2021, 25(22): 10711-23.

[35]       ZHANG Q, XUE T, GUAN J, et al. Irigenin alleviates angiotensin II-induced oxidative stress and apoptosis in HUVEC cells by activating Nrf2 pathway [J]. Drug development research, 2021, 82(7): 999-1007.

[36]       TAKESHITA K, SATOH M, II M, et al. Critical role of endothelial Notch1 signaling in postnatal angiogenesis [J]. Circulation research, 2007, 100(1): 70-8.

[37]       HAYASHI H, KUME T. Foxc transcription factors directly regulate Dll4 and Hey2 expression by interacting with the VEGF-Notch signaling pathways in endothelial cells [J]. PloS one, 2008, 3(6): e2401.

[38]       ZOU J, FEI Q, XIAO H, et al. VEGF-A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress-mediated autophagy [J]. Journal of cellular physiology, 2019, 234(10): 17690-703.

[39]       MDKHANA B, GOEL S, SALEH M A, et al. Role of oxidative stress in angiogenesis and the therapeutic potential of antioxidants in breast cancer [J]. European review for medical and pharmacological sciences, 2022, 26(13): 4677-92.

[40]       ROSSINO M G, LULLI M, AMATO R, et al. Oxidative Stress Induces a VEGF Autocrine Loop in the Retina: Relevance for Diabetic Retinopathy [J]. Cells, 2020, 9(6).

[41]       ZHONG X, YU Y, WANG C, et al. Hippocampal proteomic analysis reveals the disturbance of synaptogenesis and neurotransmission induced by developmental exposure to organophosphate flame retardant triphenyl phosphate [J]. J Hazard Mater, 2021, 404(Pt B): 124111.

[42]       ZHONG X, WU J, KE W, et al. Neonatal exposure to organophosphorus flame retardant TDCPP elicits neurotoxicity in mouse hippocampus via microglia-mediated inflammation in vivo and in vitro [J]. Archives of toxicology, 2020, 94(2): 541-52.

[43]       TARANTINI S, VALCARCEL-ARES M N, YABLUCHANSKIY A, et al. Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype [J]. The journals of gerontology Series A, Biological sciences and medical sciences, 2018, 73(7): 853-63.

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