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AOP: 509

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

Nrf2 inhibition leading to vascular disrupting effects through activating apoptosis signal pathway and mitochondrial dysfunction

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
The inhibition of Nrf2 leading to 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 Wei

Department of Toxicology, School of Public Health

Sun Yat-sen University, Guangdong, 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
Yanhong Wei   (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

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 July 04, 2024 15:46

Revision dates for related pages

Page Revision Date/Time
NFE2/Nrf2 repression June 02, 2017 16:27
Increase, Apoptosis April 15, 2017 16:17
increased,Vascular endothelial dysfunction September 01, 2021 20:37
Increase, Vascular disrupting effects August 19, 2023 20:12
Angiogenesis dysfunction August 28, 2023 05:00
Mitochondrial dysfunction April 17, 2024 08:26
Oxidative Stress March 08, 2024 12:28
NFE2/Nrf2 repression leads to Oxidative Stress July 04, 2024 15:28
Oxidative Stress leads to Increase, Apoptosis July 04, 2024 10:49
Oxidative Stress leads to Mitochondrial dysfunction May 31, 2024 17:58
Mitochondrial dysfunction leads to Increase, Apoptosis February 21, 2024 15:39
Increase, Apoptosis leads to increased,Vascular endothelial dysfunction August 28, 2023 05:49
Mitochondrial dysfunction leads to increased,Vascular endothelial dysfunction February 21, 2024 15:40
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

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

CVDs are the main cause of morbidity and mortality worldwide, increasing concern has recently brought increased attention to studies on vascular toxicity. Here, we propose putative Adverse Outcome Pathways (AOPs) of vascular disrupting effects that focuses on identifying data gaps in the mechanisms of vascular toxicity. And, the molecular initiating event (MIE) was nuclear factor (erythroid-derived 2)-like 2 (Nrf2) inhibition and the AO was vascular disrupting effects, downstream key events (KE) include oxidative stress, Activation, apoptosis signal pathway, Mitochondrial dysfunction, Vascular endothelial dysfunction and Angiogenesis dysfunction. There are many studies on toxicity mechanisms and, the evidence concerning the relationship between KEs is sufficient. The AOP framework is suitable for integrating existing data from various literature sources and identifying data gaps in vascular toxicity mechanisms.

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 inhibiting the Nrf2-signaling pathway. The abnormal expression of Nrf2 plays an important role in the vasculogenesis and angiogenesis. The postulated molecular initiating event (MIE) for this AOP, may be invoked by effects on the inhibition of Nrf2. Downstream key events (KE) include oxidative stress, Activation, apoptosis signal pathway, Mitochondrial dysfunction, Vascular endothelial dysfunction. KE relationships (KERs) leading to Angiogenesis dysfunction. 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, to better elucidate the AOP of vascular disrupting effect, 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 1417 NFE2/Nrf2 repression NFE2/Nrf2 repression
KE 1392 Oxidative Stress Oxidative Stress
KE 1365 Increase, Apoptosis Increase, Apoptosis
KE 177 Mitochondrial dysfunction Mitochondrial dysfunction
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

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

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

Sex Applicability

The sex for which the AOP is known to be applicable. More help

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. The postulated molecular initiating event (MIE) for this AOP may be invoked by effects on the inhibition of Nrf2. Downstream key events (KE) include oxidative stress,Activation, apoptosis signal pathway,Mitochondrial dysfunction, Vascular endothelial dysfunction. KE relationships (KERs) lead to Angiogenesis dysfunction, which is consistent with established biological understanding. Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with lab rats, mice, cell lines, and zebrafish. Wei et al provided some evidence, such as antagonism, knock-outs, or knock-ins to probe the necessity of MIE and KE. Furthermore, the AOP can be anticipated based on broader chemical-specific knowledge. However, more studies need to explore dose concordance, incidence concordance, and temporal concordance. 

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

Links

Human

Homo sapiens

Low

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

  1. 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. The postulated AOP may be invoked by effects on the inhibition of Nrf2. Downstream key events (KEs) include oxidative stress, activation, apoptosis signal pathway, mitochondrial dysfunction, vascular endothelial dysfunction. KE relationships (KERs) leading to angiogenesis dysfunction, which is consistent with established biological understanding. Support for the essentiality of the key events can be obtained from a wide diversity of taxonomic groups, with lab rats, mice, cell lines, and zebrafish. Wei et al provided some evidence such as antagonism, knock-outs, or knock-ins to probe the necessity of MIE and KEs. Furthermore, the AOP can be anticipated based on broader chemical-specific knowledge. However, more studies are needed to explore the dose concordance, incidence concordance, and temporal concordance. 

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.

               
  Assigned weight  Qualitative rating          
    MIE KE1 KE2 KE3 KE4 KE5
Biological plausibility Some in vivo and in vitro evidence suggest that the chemicals can cause the vascular toxicity
Essentiality empirical support 0.4 1 1 1 1 1 1
Dose and incidence concordance 0.2 3 3 3 3 3 3
Empirical support temporal concordance 0.2 3 3 3 3 3 3
Consistency across test systems 0.1 3 3 3 3 3 3
Analogy mutiple studies support KE and KER 0.1 3 3 3 3 3 3
Score 1 2.2 2.2 2.2 2.2 2.2 2.2
AOP Score 0.88            

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]        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.

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

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

[10]       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.

[11]       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.

[12]       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.

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

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

[15]       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.

[16]       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.

[17]       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.

[18]       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.

[19]       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.

[20]       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.

[21]       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.

[22]       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.

[23]       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.

[24]       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.

[25]       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.

[26]       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.

[27]       ZHENG S, WANG Y, GUO W, et al. FOXO6 transcription inhibition of CTRP3 promotes OGD/R-triggered cardiac microvascular endothelial barrier disruption via SIRT1/Nrf2 signaling [J]. Folia morphologica, 2023.

[28]       WANG D P, KANG K, SUN J, et al. URB597 and Andrographolide Improve Brain Microvascular Endothelial Cell Permeability and Apoptosis by Reducing Oxidative Stress and Inflammation Associated with Activation of Nrf2 Signaling in Oxygen-Glucose Deprivation [J]. Oxidative medicine and cellular longevity, 2022, 2022: 4139330.

[29]       ZHANG Q, LIU J, DUAN H, et al. Activation of Nrf2/HO-1 signaling: An important molecular mechanism of herbal medicine in the treatment of atherosclerosis via the protection of vascular endothelial cells from oxidative stress [J]. Journal of advanced research, 2021, 34: 43-63.

[30]       ZHANG H, YUAN B, HUANG H, et al. Gastrodin induced HO-1 and Nrf2 up-regulation to alleviate H2O2-induced oxidative stress in mouse liver sinusoidal endothelial cells through p38 MAPK phosphorylation [J]. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 2018, 51(10): e7439.

[31]       ZHANG C, KONG X, MA D. miR-141-3p inhibits vascular smooth muscle cell proliferation and migration via regulating Keap1/Nrf2/HO-1 pathway [J]. IUBMB life, 2020, 72(10): 2167-79.

[32]       YANG K, SONG H, YIN D. PDSS2 Inhibits the Ferroptosis of Vascular Endothelial Cells in Atherosclerosis by Activating Nrf2 [J]. Journal of cardiovascular pharmacology, 2021, 77(6): 767-76.

[33]       SHA W, ZHAO B, WEI H, et al. Astragalus polysaccharide ameliorates vascular endothelial dysfunction by stimulating macrophage M2 polarization via potentiating Nrf2/HO-1 signaling pathway [J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2023, 112: 154667.

[34]       LIU L, WANG R, XU R, et al. Procyanidin B2 ameliorates endothelial dysfunction and impaired angiogenesis via the Nrf2/PPARγ/sFlt-1 axis in preeclampsia [J]. Pharmacological research, 2022, 177: 106127.

[35]       LI H, ZHUANG W, XIONG T, et al. Nrf2 deficiency attenuates atherosclerosis by reducing LOX-1-mediated proliferation and migration of vascular smooth muscle cells [J]. Atherosclerosis, 2022, 347: 1-16.

[36]       ASHINO T, YAMAMOTO M, YOSHIDA T, et al. Redox-sensitive transcription factor Nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia [J]. Arteriosclerosis, thrombosis, and vascular biology, 2013, 33(4): 760-8.

[37]       WANG Q, LIU Y, GUO J, et al. Microcystin-LR induces angiodysplasia and vascular dysfunction through promoting cell apoptosis by the mitochondrial signaling pathway [J]. Chemosphere, 2019, 218: 438-48.

[38]       CHANDRA J, SAMALI A, ORRENIUS S. Triggering and modulation of apoptosis by oxidative stress [J]. Free radical biology & medicine, 2000, 29(3-4): 323-33.

[39]       SINHA K, DAS J, PAL P B, et al. Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis [J]. Archives of toxicology, 2013, 87(7): 1157-80.

[40]       WU Y, PAN B, ZHANG Z, et al. Caspase-4/11-Mediated Pulmonary Artery Endothelial Cell Pyroptosis Contributes to Pulmonary Arterial Hypertension [J]. Hypertension (Dallas, Tex : 1979), 2022, 79(3): 536-48.

[41]       LAI Y C, PAN K T, CHANG G F, et al. Nitrite-mediated S-nitrosylation of caspase-3 prevents hypoxia-induced endothelial barrier dysfunction [J]. Circulation research, 2011, 109(12): 1375-86.

[42]       DIMMELER S, ZEIHER A M. Endothelial cell apoptosis in angiogenesis and vessel regression [J]. Circulation research, 2000, 87(6): 434-9.

[43]       SZEWCZYK A, JARMUSZKIEWICZ W, KOZIEL A, et al. Mitochondrial mechanisms of endothelial dysfunction [J]. Pharmacological reports : PR, 2015, 67(4): 704-10.

[44]       DIKALOV S, ITANI H, RICHMOND B, et al. Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension [J]. American journal of physiology Heart and circulatory physiology, 2019, 316(3): H639-h46.

[45]       PENG W, CAI G, XIA Y, et al. Mitochondrial Dysfunction in Atherosclerosis [J]. DNA and cell biology, 2019, 38(7): 597-606.

[46]       DAVIDSON S M, DUCHEN M R. Endothelial mitochondria: contributing to vascular function and disease [J]. Circulation research, 2007, 100(8): 1128-41.

[47]       UNGVARI Z, TARANTINI S, KISS T, et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature [J]. Nature reviews Cardiology, 2018, 15(9): 555-65.

            [48]     ALEXANDER Y, OSTO E, SCHMIDT-TRUCKSäSS A, et al. Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on                             Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis [J]. Cardiovascular research, 2021, 117(1):                         29-42.