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

Abstract

Background: Vascular 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.

Objectives: To identify the genes and canonical pathways affected by VEGF-A inhibition in non-lesional and plaque skin ex vivo.

Methods: Total 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.

Results: VEGF-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.

Conclusion: Early 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.