Inhibition of vascular endothelial growth factor‐A downregulates angiogenesis in psoriasis: A pilot study

Luengas‐Martinez, Andrea; Ismail, Dina; Paus, Ralf; Young, Helen

doi:10.1002/ski2.245

Cited by 3 publications

References 105 publications

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Vascular endothelial growth factor A inhibition remodels the transcriptional signature of lipid metabolism in psoriasis non‐lesional skin in 12 h ex vivo culture

Luengas‐Martinez,

Ismail,

Paus

et al. 2024

Skin Health and Disease

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BackgroundVascular endothelial growth factor A (VEGF‐A)‐mediated angiogenesis is involved in the pathogenesis of psoriasis. VEGF‐A inhibitors are widely used to treat oncological and ophthalmological diseases but have not been used in psoriasis management. The molecular mechanisms underlying the effects of VEGF‐A inhibition in psoriatic skin remain unknown.ObjectivesTo identify the genes and canonical pathways affected by VEGF‐A inhibition in non‐lesional and plaque skin ex vivo.MethodsTotal RNA sequencing was performed on skin biopsies from patients with psoriasis (n = 6; plaque and non‐lesional skin) and healthy controls (n = 6) incubated with anti‐VEGF‐A monoclonal antibody (bevacizumab, Avastin®) or human IgG1 isotype control for 12 h in serum‐free organ culture. Differentially expressed genes between paired control and treated samples with adjusted p‐values <0.1 were considered significant. Gene ontology and ingenuity pathway analysis was used to identify enriched biological processes, canonical pathways and upstream regulators.ResultsVEGF‐A inhibition upregulated the expression of genes involved in lipid metabolism. Pathway enrichment analysis identified the activation of pathways involved in fatty acids and lipid biosynthesis and degradation in non‐lesional skin and ferroptosis in plaque skin. VEGF‐A inhibition downregulated endothelial cell apoptosis in non‐lesional psoriasis skin and members of the interferon family were identified as potential regulators of the effects of VEGF‐A inhibition in non‐lesional skin.ConclusionEarly response to VEGF‐A inhibition is associated with changes in lipid metabolism in non‐lesional psoriasis skin and cellular stress in psoriasis plaque. More investigation is needed to validate these findings.

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Vascular endothelial growth factor A inhibition remodels the transcriptional signature of lipid metabolism in psoriasis non‐lesional skin in 12 h ex vivo culture

Luengas‐Martinez,

Ismail,

Paus

et al. 2024

Skin Health and Disease

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Perceived stress exacerbates psoriasis in human skinin vivo: Insights from a humanized psoriasis mouse model

Zeltzer,

Keren,

Shinnawi

et al. 2024

Preprint

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The widely held belief that psychoemotional stress triggers or exacerbates psoriatic skin lesions lacks sufficient scientific evidence. This study investigated this concept using a psoriasis humanized mouse model. Healthy human skin was grafted onto SCID/beige mice (n=25), and one month later, psoriatic lesions were induced by intradermal injection of autologous, in vitro IL-2-preactivated PBMCs. Following lesion development, topical dexamethasone (DEX) was applied to induce lesion remission. After lesions disappeared, the mice were exposed to either sonic or sham stress for 24 hours. Sonic stress led to the relapse of psoriatic lesions in all human skin xenografts within 14 days. This relapse was associated with significant changes in psoriasis-related skin characteristics: increased epidermal thickness, K16 expression, keratinocyte proliferation, antimicrobial peptide expression (S100A7, hβ2-defensin), and immune activation markers (HLA-DR, ICAM-1, CD1d, MICA-NKG2D). Additionally, epidermal and dermal immune cells (CD3+, CD8+, CD11c+, CD56+, ILC3, c-KIT+ or tryptase+ cells) and psoriasis-associated pro-inflammatory mediators (CXCL10, IL-22, IL-15, IL-17A/F, IFN-γ, and TNFα) were found to be increased. Neurogenic inflammation biomarkers (NGF, NK1-R, and substance P) were also significantly upregulated in stressed mice. Treatment with the FDA-approved neurokinin-1 receptor antagonist, aprepitant, prevented stress-induced psoriatic relapses in 4 out of 5 mice and normalized most inflammatory and neurobiological markers. These findings provide novel, conclusive evidence that perceived stress can trigger psoriatic lesions in human skin xenografts in vivo and highlight the role of substance P-dependent neurogenic inflammation in this process.

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Angiogenesis in psoriasis as a therapeutic target (literature review)

Kochergin,

Brezhneva,

Yazkova

et al. 2024

Russian Journal of Skin and Venereal Diseases

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One of the characteristic features of psoriasis is increased vascularization in the psoriatic plaque. It is known that this process occurs as a result of pathological angiogenesis, which leads to an increase of blood vessels in the lesion, increased proliferation of endothelial cells, vasodilation and increased permeability of the vascular wall, facilitating penetration of immune cells and increasing inflammation. Many signaling molecules are involved in the process of angiogenesis in psoriasis. The most important indicator of the severity of pathological angiogenesis is endothelial vascular growth factor (VEGF). The issue of using blood serum analysis for VEGF and diagnostic imaging techniques of the vascular network in psoriatic plaques to determine the severity of the process and the possibility of using additional treatment directions aimed at reducing vascularization is being considered. At the moment, the mechanisms of angiogenesis in psoriasis are being actively studied, and the possibilities of therapeutic influence on this link of pathogenesis are especially interesting. The authors present an analysis of the current literature on this topic, and suggest possible available treatment strategies based on the data obtained. Further research in this direction is needed to optimize the therapy of psoriasis, the main purpose of which will be to reduce the duration of treatment and prolong the time of remission.

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Inhibition of vascular endothelial growth factor‐A downregulates angiogenesis in psoriasis: A pilot study

Cited by 3 publications

References 105 publications

Vascular endothelial growth factor A inhibition remodels the transcriptional signature of lipid metabolism in psoriasis non‐lesional skin in 12 h ex vivo culture

Vascular endothelial growth factor A inhibition remodels the transcriptional signature of lipid metabolism in psoriasis non‐lesional skin in 12 h ex vivo culture

Perceived stress exacerbates psoriasis in human skinin vivo: Insights from a humanized psoriasis mouse model

Angiogenesis in psoriasis as a therapeutic target (literature review)

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