Luengas-Martinez Andrea, Ismail Dina, Paus Ralf, Young Helen S
Centre for Dermatology Research and Manchester Academic Health Science Centre The University of Manchester Manchester UK.
Dr. Philip Frost Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami Florida USA.
Skin Health Dis. 2024 Oct 26;4(6):e471. doi: 10.1002/ski2.471. eCollection 2024 Dec.
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.
To identify the genes and canonical pathways affected by VEGF-A inhibition in non-lesional and plaque skin ex vivo.
Total RNA sequencing was performed on skin biopsies from patients with psoriasis ( = 6; plaque and non-lesional skin) and healthy controls ( = 6) incubated with anti-VEGF-A monoclonal antibody (bevacizumab, Avastin®) or human IgG isotype control for 12 h in serum-free organ culture. Differentially expressed genes between paired control and treated samples with adjusted -values <0.1 were considered significant. Gene ontology and ingenuity pathway analysis was used to identify enriched biological processes, canonical pathways and upstream regulators.
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.
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.
血管内皮生长因子A（VEGF-A）介导的血管生成参与银屑病的发病机制。VEGF-A抑制剂广泛用于治疗肿瘤和眼科疾病，但尚未用于银屑病的治疗。VEGF-A抑制对银屑病皮肤影响的分子机制尚不清楚。
在体外确定非皮损和斑块状皮肤中受VEGF-A抑制影响的基因和经典信号通路。
对银屑病患者（n = 6；斑块状皮肤和非皮损皮肤）和健康对照者（n = 6）的皮肤活检组织进行全RNA测序，这些组织在无血清器官培养中与抗VEGF-A单克隆抗体（贝伐单抗，阿瓦斯汀®）或人IgG同型对照孵育12小时。校正后P值<0.1的配对对照样本和处理样本之间的差异表达基因被认为具有统计学意义。使用基因本体论和 Ingenuity 通路分析来确定富集的生物学过程、经典信号通路和上游调节因子。
VEGF-A抑制上调了参与脂质代谢的基因表达。通路富集分析确定了非皮损皮肤中参与脂肪酸和脂质生物合成及降解的信号通路以及斑块状皮肤中铁死亡相关信号通路的激活。VEGF-A抑制下调了非皮损银屑病皮肤中的内皮细胞凋亡，并且干扰素家族成员被确定为非皮损皮肤中VEGF-A抑制作用的潜在调节因子。
对VEGF-A抑制的早期反应与非皮损银屑病皮肤中脂质代谢的变化以及银屑病斑块中的细胞应激有关。需要更多研究来验证这些发现。
