Angiogenesis as a novel target for the management of psoriasis

Abstract

Chronic plaque psoriasis is an immune-mediated systemic disease characterised by skin lesions and caused by a combination of genetic and environmental factors. Aberrant keratinocyte proliferation and differentiation, enhanced immune response and angiogenesis underlie the pathogenesis of psoriasis. Vascular endothelial growth factor A (VEGF-A) induces inflammatory angiogenesis in psoriasis and is overexpressed in the skin and plasma of patients with psoriasis. There is preclinical evidence and a few case reports supporting the potential of anti-VEGF-A treatment strategies in psoriasis. Despite the wealth of evidence regarding the potential of targeting VEGF-A in psoriasis, the effects of VEGF-A inhibition in psoriasis remain underexplored. The first aim of this project was to develop a model for the study of VEGF-A blockade in human skin ex vivo. The second aim was to characterise the effects of VEGF-A inhibition in the skin of patients with psoriasis. Lastly, we investigated the association between disease severity, levels of VEGF-A and response to VEGF-A inhibition. An organ culture model for the study of VEGF-A blockade in healthy human skin ex vivo was developed using a monoclonal antibody for VEGF-A (bevacizumab, Avastin). VEGF-A inhibition induced endothelial cell apoptosis in healthy human skin ex vivo at 72 hours. Healthy skin organ culture media and supplements were adapted to meet the different requirement of psoriasis skin ex vivo. Bevacizumab downregulated angiogenesis in psoriasis plaque skin ex vivo demonstrating the potential of anti-VEGF-A therapy to downregulate angiogenesis in psoriasis. Angiogenesis downregulation was more substantial in volunteers with severe psoriasis and high levels of VEGF-A in plasma and in the skin, suggesting that anti-VEGF-A therapy is more likely to benefit this subgroup of patients with psoriasis. Bevacizumab downregulated endothelial cell apoptosis in psoriasis non-lesional skin ex vivo, suggesting a protective mechanism against apoptosis in the cutaneous vasculature of psoriasis non-lesional skin ex vivo. The increase of tryptase+ mast cells in psoriasis plaque skin, suggests that VEGF-A inhibition may affect mast cell activation in psoriasis plaque skin ex vivo. To identify the molecular mechanisms underlying bevacizumab-mediated effects upon the cutaneous vasculature in psoriasis plaque and psoriasis non-lesional skin, RNA sequencing was employed, revealing signalling pathways involved in lipid biosynthesis as a major downstream target in psoriasis non-lesional skin. In conclusion, a model for the study of VEGF-A blockade in human skin ex vivo is presented. The utility of VEGF-A inhibition to downregulate angiogenesis in psoriasis plaque skin ex vivo is demonstrated for the first time. Data presented here demonstrate that VEGF-A-targeting therapies are a promising therapeutic strategy for psoriasis and they could be especially useful in patients with severe psoriasis and with high levels of VEGF-A.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Helen Young (Supervisor) & Ralf Paus (Supervisor)