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Excessive angiogenesis associated with psoriasis as acause for cardiovascular ischaemiaDOI:10.1111/exd.13310

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Citation for published version (APA):Malecic, N., & Young, H. S. (2017). Excessive angiogenesis associated with psoriasis as a cause forcardiovascular ischaemia. Experimental Dermatology, 26(4), 299-304. https://doi.org/10.1111/exd.13310

Published in:Experimental Dermatology

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Download date:25. Mar. 2021

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Excessive angiogenesis associated with psoriasis as a cause for cardiovascular ischaemia

Journal: Experimental Dermatology

Manuscript ID EXD-14-0219.R3

Manuscript Type: Viewpoint

Date Submitted by the Author: n/a

Complete List of Authors: Malecic, Nina; The University of Manchester, Manchester Academic Health Science Centre, Department of Dermatology Young, Helen; The University of Manchester, Manchester Academic Health Science Centre, Department of Dermatology

Keywords: Psoriasis, Vascular endothelial growth factor, Angiogenesis, Cardiovascular disease, Atherosclerosis

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1

Excessive angiogenesis associated with psoriasis as a cause for cardiovascular

ischaemia

Nina Malecic and Helen S Young (orcid.org/0000-0003-1538-445X)

The University of Manchester, Manchester Academic Health Science Centre, Department of

Dermatology, Manchester, UK

Corresponding Author:

Dr. Helen Young,

Department of Dermatology,

Salford Royal Hospital,

Manchester,

M6 8HD, UK.

Email: Helen.s.young@manchester.ac.uk

Key words: psoriasis, vascular endothelial growth factor, angiogenesis, cardiovascular

disease, atherosclerosis

Funding source

None

Conflict of interest

No conflict of interest to declare

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Abstract

Psoriasis, a common disease affecting 2-3% of the UK population, produces significant

impairment of quality of life and is an immense burden on sufferers and their families.

Psoriasis is associated with significant cardiovascular co-morbidity and the metabolic

syndrome. Angiogenesis, a relatively under-researched component of psoriasis, is a key

factor in pathogenesis of psoriasis and also contributes to the development of

atherosclerosis. Vascular endothelial growth factor (VEGF) is a well established mediator of

pathological angiogenesis which is upregulated in psoriasis. It is possible that, in patients

with psoriasis, cutaneous angiogenesis may be both a marker for systemic vascular

pathology and a novel therapeutic target. In this viewpoint paper the role of VEGF mediated

angiogenesis as a cause for cardiovascular events in patients with psoriasis is explored.

Introduction

Psoriasis is a common, immune-mediated inflammatory disease that occurs in 2-3% of the

population of the UK1. In early-onset psoriasis, developing before the age of 40 years (Type

1 psoriasis)2 and accounting for over 75% of patients, genetic predisposition in conjunction

with an environmental trigger, such as infection or stress, is important for disease

expression1.

Psoriasis is associated with an increased risk of cardiovascular disease (CVD) and patients

with psoriasis develop major adverse cardiovascular events more frequently than individuals

without psoriasis. A prospective population based cohort study in British patients with

psoriasis reported that after adjustment for traditional cardiovascular risk factors; patients with

severe psoriasis had an increased relative risk of myocardial infarction and that psoriasis was

an independent risk factor for CVD3. In addition, there is strong evidence that patients with

psoriasis are more frequently affected by components of the metabolic syndrome (traditional

risk factors for CVD) than healthy controls3,4. Although, the high prevalence of traditional risk

factors for CVD in patients with psoriasis raises the possibility that the disease per se may not

be an independent risk factor for CVD – the “intrinsic” psoriasis-related CVD risk, deserves

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further investigation at the molecular level5,6. Although a number of explanatory models,

mostly related to the underlying inflammatory process, have been experimentally

documented, angiogenesis as direct disease-related influence on CVD risk in psoriasis is

relevant and merits further consideration.

Angiogenesis, the formation of new blood vessels from a pre-existing vascular bed, is a

significant component of the pathogenic mechanisms involved in tumour growth and

metastasis, arterosclerosis and psoriasis7,8. Vascular endothelial growth factor (VEGF; also

known as VEGFA) produced by epidermal keratinocytes promotes angiogenesis, enhances

vascular permeability7 and is upregulated in psoriasis8,9.

Atherosclerosis is the primary cause of coronary artery disease and stroke in western

populations10. Evidence suggests that angiogenesis of the arterial vasa vasorum is a key

factor in the growth and subsequent destabilisation of atherosclerotic plaques11. VEGF, in

conjunction with other cytokines, has an important function in co-ordinating and promoting the

growth of the atherosclerotic plaque (Figure 1)12. In this paper the role of VEGF mediated

angiogenesis in the development of both psoriasis and atherosclerosis is discussed with key

evidence summarised in Table 1. A key role for VEGF as a mediator of cardiovascular co-

morbidity in patients with psoriasis is postulated.

Cardiovascular disease (CVD), Angiogenesis and VEGF

Atherosclerosis is an inflammatory process, characterised by a progressive series of events

within the arterial wall10. Initially lipid accumulation in the arterial wall produces a fatty streak,

subsequent infiltration by monocytes produces the lipid core of the atheromatous plaque10.

Advanced atheromatous plaques can cause local obstruction of the arterial lumen or they can

destabilise and rupture10,12. Ruptured atherosclerotic plaques cause 75% of the total fatal

acute myocardial infarction cases reported in the Western world13.

Although the pathogenesis of atherosclerosis has been extensively investigated the key

question of how an asymptomatic stable atherosclerotic plaque is transformed into a high-risk

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lesion capable of rupture remains unanswered12. Over the last decade clinical investigation

has focused on identifying the morphology and characteristics of stable versus vulnerable

plaques14-16 whereas animal studies have investigated the mechanisms of plaque

destabilisation17-20. VEGF mediated angiogenesis appears to play crucial role in the

progression from stable atherosclerosis to rupture-prone lesions16 and recently a disease

progression model of angiogenic regulation of vulnerable plaque development was

postulated12. The key features of this model are detailed below and schematically outlined in

Figure 1.

The healthy arterial wall receives oxygen by diffusion from the vessel lumen. In early

atherosclerosis the expanded extracellular matrix results in thickening of the vessel intima

and oxygen diffusion becomes insufficient to meet metabolic demand. Consequently,

expression of hypoxic-inducible factor (HIF) promotes local angiogenesis21,22. HIF is a

transcription factor which is made up of two sub-units, a HIF-1β subunit and a hypoxic

responsive subunit HIF-1α. Migration of the HIF-1α-β dimer to the nucleus initiates

upregulation of multiple angiogenic factors, including VEGF21. In a physiological context, this

up-regulation of angiogenesis can be helpful in restoring vessel wall normoxia, removal of

intimal fat and the regression of atherosclerosis21.

In progressive atherosclerosis, vascular inflammation causing increased metabolic demand

for oxygen and local hypoxia due to increased arterial intima thickness results in a sustained

trigger for angiogenesis21,23. An animal model of atherosclerosis - the hypercholesterolaemic

apolipoprotein E-deficient (ApoE_/_) mouse - provided the first direct evidence that

angiogenesis was involved in the progression and pathogenesis of atherosclerosis by

demonstrating that endothelium-specific inhibitors of angiogenesis, endostatin and angiostatin

reduce plaque area and atherosclerosis24. The extent of new vessel formation within

atheromatous plaques is directly related to rupture susceptibility23,25. Studies have identified

that vasa vasorum expansion from the adventitia into the arterial intima is increased 2-fold in

advanced atherosclerotic lesions and 4-fold in ruptured lesions, as compared to stable

plaques16.

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Levels of VEGF in lesions of atherosclerosis have been observed to rise during disease

progression12,26-27. Notch and fibroblast growth factor (FGF) signalling are important

pathways which regulate and synergise VEGF-induced angiogenesis in the early phase of

vulnerable plaque development28,29. Subsequently, survival and expansion of the intra-plaque

vascular network is facilitated by angiopoietin-(Ang)130-32. VEGF and other cytokines recruit

inflammatory cells into the plaque via the luminal endothelium and the newly formed

microvasculature. Chemotaxis of CD16+ monocytes can further augment plaque progression

and vulnerability33. As the inflammatory state of the vulnerable plaque increases key

molecular triggers such as TNF-α in conjunction with persistently high levels of VEGF effects

a switch in Ang stimulation toward Ang-2-dominated signalling12,34. This promotes further

inflammation by activation of adhesion molecules on the endothelial cell membrane and

through repression of eNOS-mediated atheroprotection35-37. Loss of cell-cell junctional

integrity permits extravasation of white blood cells and leakage of erythrocytes into the plaque

of atheroma12. Finally, impaired Platelet-Derived Growth Factor (PDGF) B /PDGF Receptor

(PDGFR) signalling results in diminished pericyte coverage of the intraplaque microvessels

which can haemorrhage and cause rupture of the plaque38.

These observations support a role for angiogenesis causing atheromatous plaque growth

beyond a critical thickness - intimal thickening may have an initial angiogenesis-independent

phase, followed by an angiogenesis-dependent phase39. VEGF concentration is critical in

determining biological outcomes in vivo40. VEGF in low concentration appears to be cardio-

protective whereas, high concentrations of VEGF are pro-atherogenic11,40.

The VEGF gene is polymorphic and the two most commonly occurring single nucleotide

polymorphisms (SNPs) in the promoter and 5’ untranslated region have been associated with

regulation of VEGF production41,42. Several studies have identified polymorphisms from this

region of the VEGF gene may modulate clinical outcome in a variety of angiogenesis-

dependent diseases43-47. An association between polymorphisms / haplotypes from this key

area of the VEGF gene and the development of atherosclerosis was observed in a large UK

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cohort48. This study hypothesised that genetic regulation of VEGF expression could be a

pivotal risk / protective factor in the pathogenesis of atherosclerosis48. Similarly, a sub-study

of the Metoprolol CR/XL Randomised Intervention Trial in Heart Failure (MERIT/HF),

identified an association between the VEGF +405 CC polymorphism and poor prognosis in

patients with chronic heart failure (CHF)49. The authors speculated that insufficient

production of VEGF / angiogenesis consequent upon VEGF gene variation could influence

the pathophysiology of CHF49.

Psoriasis and Angiogenesis

Microvascular changes in plaques of psoriasis include pronounced dilation, increased

permeability and endothelial cell proliferation within the venous limb of capillaries in the

superficial dermis50,51. This increased upper dermal vascularity is evident clinically as the

Auspitz sign where successive removal of psoriatic scales reveal numerous small bleeding

points where the thinned suprapapillary epithelium has been torn off to expose the elongated,

dilated and tortuous papillary capillaries.

Examination of the skin has demonstrated that structural change in the cutaneous capillary

bed is the first (visible) step in the pathogenesis of psoriasis52,53,54. Excessive capillary-

venular dilatation precedes development of inflammation in patients with psoriasis and

resolution of these vascular changes heralds clearance of plaques of psoriasis55. Vascular

expansion in plaques of psoriasis is limited to vascular enlargement, increased tortuosity and

elongation rather than new growth per se from the pre-existing vascular bed – the term

inflammatory angiogenesis has been coined to describe this phenomenon. Histological study

of early lesions of psoriasis has established that these changes are due to variation in

amounts of VEGF isoforms within the skin56. In addition, the cytokine responsiveness of

microvascular endothelial cells is altered in psoriasis in a pattern, which mimics the plaque

type configuration and epidermal involvement of individual lesions57.

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VEGF is produced predominantly by keratinocytes in both the clinically involved and

uninvolved skin of patients with stable, chronic plaque psoriasis8 and TGF-α potently

upregulates VEGF levels in a paracrine fashion8,9,58-60. VEGF and endothelial cell stimulating

angiogenesis factor, are significantly elevated in plaques of psoriasis and that these levels

appear to correlate with clinical severity9. Overexpression of VEGFR-1 and VEGFR-2

receptors in dermal microvascular endothelium has been reported in psoriasis8, healing skin

wounds61 and delayed hypersensitivity reactions62. Furthermore, elevated levels of VEGF

have been reported in the plasma of patients with erythrodermic psoriasis63 and it has been

reported that patients with moderate-severe or severe psoriasis have plasma VEGF levels

that are significantly increased during relapse of psoriasis as compared with remission64.

Plasma levels of VEGF are also significantly increased in patients with stable chronic plaque

psoriasis65.

The VEGF gene is located on chromosome 6 at 6p21, close to PSORS 1 a known

chromosomal locus for psoriasis susceptibility66. VEGF genotype distinguishes two groups of

patients with psoriasis - “high” and “low” VEGF producers68,69. The “high VEGF producing”

genotypes show significant association with early-onset psoriasis and development of severe

disease whereas the “low VEGF producing” genotypes show no association with psoriasis.

These findings suggest that the “angiogenetic constitution” of an individual might influence

both psoriasis susceptibility and phenotype such that those individuals with “high VEGF

producing” genotypes could manifest a “pro-angiogenic” psoriasis phenotype65,69,70.

VEGF-transgenic mice, which overexpress VEGF in the epidermis have vascular expansion

within the superficial dermis71. The chronic inflammatory response mediated by constitutive

VEGF expression, in mice homozygous for the VEGF transgene, bears a resemblance to key

features of psoriasis morphologically, histologically and immunologically72. This psoriasis-like

phenotype can be reversed by treatment with a potent VEGF receptor antagonist - VEGF-

Trap – suggesting that maintenance of psoriasis-like chronic inflammation is a VEGF

dependent process72.

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Molecular mechanisms common to both atherosclerosis and psoriasis.

Psoriasis and atherosclerosis have many similarities in their underlying pathophysiology

including key stimuli / initiating events, cytokines and molecular signalling pathways73.

In the early stages of development of both psoriasis and atherosclerosis, stimuli such as local

hypoxia trigger the release of proangiogenic factors including hypoxia inducible factor-1 (HIF-

1) 74-75. Hypoxia may result from increased oxygen demand or decreased oxygen supply as a

consequence of active inflammation or increasing diffusion distance in a thickening psoriasis

or atheromatous plaque. Thereafter, expression of further pro-angiogenic cytokines, including

VEGF, results in the formation of new vessels and facilitates leukocyte transmigration into

areas of inflammation via enhanced expression of cell adhesion molecules55,71. Inflammatory

cells such as macrophages and T lymphocytes infiltrate the skin or vessel wall through these

newly formed capillaries, effecting release of a number of pro-inflammatory cytokines many of

which have pro-angiogenic effects, including IL-8, TNF-α, and IL-1776-77. These observations

have led to suggestion that in addition to similarities in the angiogenic pathway between

atherosclerosis and psoriasis, oxidative stress is also a key area of commonality between

both pathologies73. Oxidised phospoholipids (OxPL) are key promoters of angiogenesis in

atherosclerosis which stimulate transcription of other pro-angiogenic and pro-inflammatory

mediators. OxPL also upregulate VEGF expression from keratinocytes, suggesting a

potential role in psoriasis angiogenesis78. Ischaemia is a key metabolic determinant for ROS

production for both diseases and the main enzymatic sources of ROS are similar for both

conditions. Increased production of ROS and upregulation of HIF-1α results in activation of

the JAK-STAT, NF-kB, and MAPK signaling pathways, which have been implicated in the

promotion of both psoriasis and cardiovascular disease73.

There is a growing body of evidence to support Wnt signalling involvement in many key

aspects of atherosclerotic lesion development, from the initially dysfunctional endothelium to

the vascular remodelling observed following myocardial infarction79. There is altered

expression of Wnt signalling proteins in patients with psoriasis including a five-fold

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upregulation of Wnt5A transcripts accompanied by increased Wnt-5a protein levels in lesional

skin. Expression of Frizzled 2 (FZD2) and FZD5, which encode receptors for Wnt5A have

also been reported as increased in lesional psoriatic skin. Studies has evidenced a shift

towards noncanonical Wnt signalling pathways in psoriasis accompanied by impairment of

the homeostatic inhibition of Wnt signalling by Wnt inhibitory factor (WIF)-1 and dickkopf80.

The Notch signalling pathway is important in regulating both physiological and pathological

angiogenesis28,81. Notch modulation of VEGF signalling has also been described28. Notch

ligand DLL4-Notch signalling is specifically upregulated in the proliferating micro-vessels of

atherosclerotic plaques that are vulnerable to rupture29. Notch signalling can modulate the

inflammatory response of vulnerable atherosclerotic lesions and DLL4 blockade can diminish

further plaque development in a murine model of atherosclerosis82. Notch signalling has

been identified as a coordinating factor in VEGF mediated angiogenesis in psoriatic arthritis83

and may influence the fate and differentiation of T cells in patients with psoriasis84.

Opportunity for novel treatment strategies.

Controlling pathological angiogenesis by regulating inappropriately activated VEGF / VEGFR-

2 is a potential therapeutic strategy for the treatment of vascular diseases85. Clinically,

plasma levels of VEGF have been shown to predict adverse cardiac events in patients with

known atherosclerosis86. The amount of VEGF in plaques of psoriasis has been shown to

correlate with clinical severity of disease9. It is possible that upregulation of VEGF secondary

to one disease process may influence or worsen the other. The likely time-course of the

development of these parallel pathologies is speculative but worthy of further research. TNF-

α has been shown to function as an upstream inducer of several pro-angiogenic pathways.

Anti-TNF-α therapy can downregulate levels of many inflammatory cytokines within psoriatic

plaques, including the angiogenic cytokines Ang 1 and 2 and their receptor Tie287. There is

emerging evidence demonstrating improvement in cardiovascular outcomes in inflammatory

disease such as rheumatoid arthritis following treatment with TNF-α inhibitors88,89.

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Existing VEGF inhibitors target the VEGF pathway in various ways including: i) direct

inhibition of VEGF protein (anti-VEGF monoclonal antibodies - bevacizumab and

ranibizumab); ii) prevention of VEGF receptor binding (VEGF receptor antagonists -

alfibercept/VEGF-Trap and pegaptanib) and; iii) inhibition of VEGF receptor function through

inhibition of tyrosine kinase (tyrosine kinase inhibitors (TKIs) - sunitinib, sorafenib, vandetanib

and pazopanib) 90,91. To date there are reports of five patients with psoriasis who were

receiving treatment for malignancy with the VEFG inhibitors bevacizumab92,93, sunitinib94, and

sorafenib95 who demonstrated improvement in their psoriasis. These clinical observations

have also been replicated in animal models where dual inhibition of VEGFR-1 and VEGFR-2

(using the fusion-protein Aflibercept (Eylea™, Regeneron Pharmaceuticals, also known as V-

trap)) achieved significant amelioration of a psoriasis-like phenotype in transgenic VEGF

mice72. Furthermore, antiangiogenic (non-viral somatic) gene therapy was highly efficacious

both in the prevention and treatment of psoriasis lesions in vivo by inhibiting angiogenesis

and reduces the number and size of the microvessels in the skin96. Recent work published in

Experimental Dermatology identified a novel small-molecule inhibitor of VEGF / VEGFR-2

which demonstrated potent anti-angiogenic activity in both in vitro and in vivo investigations85.

It is important to note that the VEGF inhibitors in current clinical use are associated with a

number of potentially serious side effects including hypertension, left ventricular dysfunction

and gastrointestinal perforation – a risk/benefit analysis which might be unfavourable for

patients with psoriasis90,91.

Conclusions

VEGF mediated angiogenesis is central to both the development of psoriasis and

arterosclerosis and may contribute to the propensity for certain individuals to develop both

conditions. It is possible that, genetically determined “high VEGF production” may drive

expression of a severe psoriasis phenotype and contribute to the development of

cardiovascular co-morbidity in a sub-group of patients with psoriasis.

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Assessment of cutaneous vascularity in psoriasis could be a key determinant for disease

prognosis and ultimately health outcomes for patients with psoriasis. Vascular signatures in

both the skin and within the arterial vasa vasorum could be key in the design of personalised

treatment regimens for patients.

Acknowledgements

The authors acknowledge the work of all who have contributed to this field and apologise to

those investigators whose work has not been cited due to space and citation restrictions.

Nina Malecic and Helen Young designed, wrote and approved the manuscript.

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Figure Legend

Figure 1

A diagrammatic illustration of the recently proposed disease progression model of angiogenic

regulation of vulnerable plaque development12. VEGF is a key driver of angiogenesis in all

phases of the disease.

Panel 1 (Phase 1) – thickening of the vessel intima results in expression of hypoxic-inducible

factor (HIF) and promotion of local Vascular Endothelial Growth Factor (VEGF)-mediated

angiogenesis.

Panel 2 (Phase 2) – persistently high levels of VEGF facilitates a switch in angiopoietin (Ang)

stimulation toward Ang-2-dominated signalling.

Panel 3 (Final phase) - impaired Platelet-Derived Growth Factor (PDGF) B /PDGF Receptor

(PDGFR) signalling results in diminished pericyte coverage of the intraplaque microvessels

which can haemorrhage and promote rupture of the plaque.

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Table 1

Key similarities between psoriasis and atheroscelerosis

PSORIASIS

ATHEROSCLEROSIS

Angiogenesis in the dermis of lesional skin

Intra-plaque angiogenesis

Plasma levels of VEGF are significantly increased in patients with i) psoriasis65, ii) erythrodermic psoriasis61 and iii) during relapse of psoriasis as compared with remission62

The extent of new vessel formation within atheromatous plaques is directly related to rupture susceptibility23,25

Levels of VEGF, produced by keratinocytes,

are significantly elevated in plaques of psoriasis8 and correlate with clinical severity9

Levels of VEGF in plaques of atherosclerosis rise during disease progression12,26-27

VEGF genotype distinguishes two groups of patients with psoriasis - “high” and “low” VEGF producers69

VEGF promoter polymorphisms are associated with the development of atherosclerosis and may regulate progression of disease48

The “high VEGF producing” genotype (+405 CC) is associated with early-onset psoriasis and development of severe disease65,69,70

The VEGF +405 CC genotype is associated with poor prognosis in patients with chronic heart failure (CHF)49

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Growth of tunica intima of blood vessel wall

Hypoxia in core region of blood vessel wall

Adventitial microvascular response

Induction of angiogenic sprouting of tip and stalk cell structures

FGFR activation

Notch DLL4

FGF1 and FGF2

Proliferation and migration of endothelial cells

Synergy with VEGF

Promoted by VEGF

Survival and expansion of neovasculature

Inflammatory cells enter via luminal epithelium and neovasculature

Amplification of plaque inflammation

Increased Ang1/Ang2 ratios

Activation of adhesion molecules and loss of cell to cell junction integrity

Further amplification of plaque inflammation

Promoted by VEGF

Promoted by VEGF

Promoted by VEGF

Promoted by VEGF

Inflammatory triggers

Production of VEGF

High levels of Ang1, FGF and VEGF

Recruitment by VEGF

Impaired mural cell recruitment via PDGFB in neovasculature

Absence of mural cell coverage in plaque microvessels

Lack of inhibition of VEGF by PDGF causes reduced endothelial cell permeability

Diminished pericyte-endothelial cell contact

Hyperproliferation and functional dedifferentiation of endothelial cells

Further weakening of the advanced lesion and tortuous microvessels with increased susceptibility to intraplaque haemorrhage

Promoted by VEGF

Promoted by VEGF

Promoted by VEGF

Phase 1 Phase 2 Phase 3

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