THU0059 Decreased Expression of Neuropilin-1 in Systemic Sclerosis: Potential Contribution to Impaired Angiogenesis. (23rd January 2014)

• Record Type: Journal Article
• Authors: Romano, E.; Manetti, M.; Mazzotta, C.; da Silva Cora, I. J.; Bellando-Randone, S.; Ibba-Manneschi, L.; Matucci-Cerinic, M.; Guiducci, S.
• Is Part Of: Annals of the rheumatic diseases. Volume 72:Supplement 3(2013)
• Page Start: A183
• Page End: A183
• Publication Date: 2014-01-23
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2013-eular.587
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disorder characterised by widespread microangiopathy, fibrosis and autoimmunity. Vascular damage is a primary event in SSc and is characterised by vascular tone dysfunction and increased circulating levels of vascular endothelial growth factor (VEGF). Neuropilins (NRPs) were origi­nally identified as adhesion molecules in the nervous system and subse­quently rediscovered as receptors for the class-3 semaphorin (sema) family of axon guidance molecules and as blood vessel receptors for VEGF. NRP1 is required for optimal VEGF/VEGFR-2 signalling, and NRP1–deficient mice exhibit vascular defects including disorganised blood vessels, lack of normal branching and missing capillary networks. Soluble NRP1 (sNRP1) may regulate VEGF/VEGFR-2 interactions. Sema3a is reported to control physiological and pathological angiogenesis. Objectives: To investigate the possible involvement of the sema3a/NRP1 axis in SSc. Methods: Circulating levels of soluble NRP1 (sNRP1) and sema3a were measured by sandwich ELISA in serum samples from SSc patients (n=49, mean±SDage: 64± 10years) and age- and sex-matched healthy controls (n=39, mean±SDage: 58± 14years). sNRP1 and sema3a levels were expressed as median and range and compared by Mann-Whitney U test. Differences were considered significant for p values less than 0.05. NRP1 protein expression was evaluated by immunohistochemistry in skin biopsies from SSc patiens (n=10) and healthy controls (n=8). Western blot was used to measure NRP1 expression in human dermal microvascular endothelial cells (H-MVECs) isolated from 3 healthy subjects at basal condition and after stimulation with recombinant human VEGF165 (10 ng/ml), SSc sera (n=3) and healthy sera (n=3) for 24h. Results: Serum levels of sNRP1 were significantly higher in healthy controls (median 0.69 ng/ml, range 0.00-2.49 ng/ml) than in SSc patients (median0.22 ng/ml, range 0.00-3.12 ng/ml) (p=0.005). No significant differences in serum levels of sema3a were detected between SSc patients (median2.07 ng/ml, range 0.13-16.4 ng/ml) and healthy controls (median 3.86 ng/ml, range 0.03-11.69 ng/ml). The expression of NRP1 was decreased in clinically affected skin biopsies from SSc patients compared with healthy skin, especially in dermal endothelial cells and stromal cells. Stimulation with VEGF165 strongly upregulated NRP1 expression in H-MVECs. The expression of NRP1 in H-MVECs was higher after treatment with healthy sera compared with basal condition, while it was decreased after challenging with SSc sera. Conclusions: Our findings suggest that NRP1 might play a role in the vascular damage and impaired angiogenic process characteristic of SSc. Disclosure of Interest: None Declared