Vascular endothelial growth factors and angiopoietins as new players in mastocytosis

Abstract

Mastocytosis is a disorder characterized by the abnormal proliferation and/or accumulation of mast cells in different organs. More than 90% of patients with systemic mastocytosis have a gain-of-function mutation in codon 816 of the KIT receptor on mast cells (MCs). The symptoms of mastocytosis patients are related to the MC-derived mediators that exert local and distant effects. MCs produce angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (ANGPTs). Serum concentrations of VEGF-A, VEGF-C, VEGF-D, ANGPT1 and ANGPT2 were determined in 64 mastocytosis patients and 64 healthy controls. Intracellular concentrations and spontaneous release of these mediators were evaluated in the mast cell lines ROSAKIT WT and ROSA KIT D816V and in human lung mast cells (HLMCs). VEGF-A, ANGPT1, ANGPT2 and VEGF-C concentrations were higher in mastocytosis patients compared to controls. The VEGF-A, ANGPT2 and VEGF-C concentrations were correlated with the symptom severity. ANGPT1 concentrations were increased in all patients compared to controls. ANGPT2 levels were correlated with severity of clinical variants and with tryptase levels. VEGF-A, ANGPT1 and VEGF-C did not differ between indolent and advanced mastocytosis. ROSAKIT WT, ROSAKIT D816V and HLMCs contained and spontaneously released VEGFs and ANGPTs. Serum concentrations of VEGFs and ANGPTs are altered in mastocytosis patients.

Neutrophil Extracellular Traps, Angiogenesis and Cancer

“…Vascular endothelial growth factors (VEGFs), including VEGF-A, VEGF-B, and placental growth factors (PlGF) are the most important angiogenic factors [ 108 ]. These factors exert their biological activities through the activation of two tyrosine kinase receptors, VEGFR1 and VEGFR2, on blood endothelial cells [ 109 , 110 ]. VEGF-C and VEGF-D promote lymphangiogenesis through the engagement of VEGFR3 on lymphatic endothelial cells [ 111 , 112 ].…”

“…VEGF-C and VEGF-D are key regulators of lymphangiogenesis by activation of the VEGFR3 receptor on lymphatic endothelial cells (LECs) [ 141 ]. Previous studies have demonstrated that tissue-resident immune cells, such as human macrophages [ 142 , 143 ] and mast cells [ 110 , 112 , 144 ], are a major source of lymphangiogenic factors. When we investigated the effects of sPLA 2 on the release of lymphangiogenic factors from human neutrophils, we found that these cells do not express VEGF-C/VEGF-D mRNAs.…”

Mast Cell–Tumor Interactions: Molecular Mechanisms of Recruitment, Intratumoral Communication and Potential Therapeutic Targets for Tumor Growth

“…For example, PGE2 induces the synthesis of VEGFA via the EP2 receptor in human cord blood-derived human MCs (CBMCs) [225]. Finally, it is important to mention that recent reports suggest that VEGF and other tumor-produced factors (such as angiopoietins 1 and 2) are associated with MC proliferation since those mediators were found to increase in serum from patients with mastocytosis [226]. The mentioned evidence suggests that intratumoral VEGF could promote MCs' survival to sustain angiogenesis and, more importantly, that factors that lead to MCs' survival maintain the production of VEGF necessary for malignant tumor growth.…”

Biologics and Airway Remodeling in Severe Asthma

“…Human lung mast cells (HLMCs) are important lung-resident immune cells involved in asthmatic airway remodeling 62 . IgE-and non-IgE-mediated activation of HLMCs induces the release of several pro-fibrotic cytokines (e.g., IL-13 and TNF-α), as well as inflammatory mediators (e.g., PGD 2 and tryptase) 63 . Tryptase induces fibroblast, endothelial and epithelial cell proliferation, further fueling airway remodeling in asthmatic individuals 64 .…”