Scientists report that targeting vascular endothelial growth factor A (VEGFA) signaling in the epidermis prevents psoriasis development. VEGFA, the principal factor responsible for the formation of new blood vessels, is known to play a key role in promoting the skin condition.
The research team, led by Cédric Blanpain, MD/PhD, WELBIO investigator and professor at the Université libre de Bruxelles, used a mouse model overexpressing VEGFA, which induces a psoriatic like disease recapitulating the hallmarks of human psoriasis. By combining VEGFA overexpression and the genetic deletion of VEGFA receptor (VEGFR1) and co-receptor (Nrp1) in the skin epidermis, the scientists, who published a paper (“Epidermal autonomous VEGFA/Flt1/Nrp1 functions mediate psoriasis-like disease”) in Science Advances, demonstrated that the deletion of Nrp1 or Flt1 prevents psoriasis development.
“Psoriasis is a common chronic skin disorder characterized by keratinocyte hyperproliferation with altered differentiation accompanied by inflammation and increased angiogenesis. It remains unclear whether the first events that initiate psoriasis development occur in keratinocytes or inflammatory cells. Here, using different psoriasis mouse models, we showed that conditional deletion of Flt1 or Nrp1 in epidermal cells inhibited psoriasis mediated by Vegfa overexpression or c-Jun/JunB deletion. Administration of anti-Nrp1 antibody reverted the psoriasis phenotype,” the investigators wrote.
“Using transcriptional and chromatin profiling of epidermal cells following Vegfa overexpression together with Flt1 or Nrp1 deletion, we identified the gene regulatory network regulated by Vegfa/Nrp1/Flt1 during psoriasis development and uncovered a key role of Fosl1 in regulating the chromatin remodeling mediated by Vegfa overexpression in keratinocytes. In conclusion, our study identifies an epidermal autonomous function of Vegfa/Nrp1/Flt1 that mediates psoriatic-like disease and demonstrates the clinical relevance of blocking Vegfa/Nrp1/Flt1 axis in psoriasis.”
“It was very surprising to find that inhibiting VEGFA signaling only in the epidermis was sufficient to completely prevent psoriasis development including immune cell infiltration and increase in blood vessel formation mediated by VEGFA overexpression,” commented Farida Benhadou, an MD/PhD student, and the first author of this study.
To assess whether inhibiting Nrp1/Vegfa interaction can be of therapeutic relevance for the treatment of psoriasis, Benhadou and colleagues administrated a therapeutic anti-Nrp1 antibody that blocks the interaction between Vegfa and Nrp1 to mice presenting psoriasis. Administration of Nrp1 blocking antibodies induced a rapid disappearance of psoriatic lesions. “These data demonstrate the therapeutic benefit of blocking Vegfa/Nrp1 interaction in the treatment of psoriatic disease, which may be safer for the treatment of psoriasis as compared to other therapeutic modalities that can be associated with serious side effects,” added Blanpain, the senior author of this study.
Altogether this new study demonstrates the essential role of Flt1 and Nrp1 expression in the skin epidermis to mediate psoriasis development, noted the researchers, pointing out that the results of this study have important implications for the understanding of mechanisms leading to psoriasis, one of the most frequent inflammatory diseases, and for the treatment of patients with psoriasis.
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