Vascular endothelial growth factors and angiopoietins as new players in mastocytosis

Simone Marcella,Luca Modestino,Amato De Paulis,Francesca Wanda Rossi,Anne Lise Ferrara,Angelica Petraroli,Mariantonia Braile,Roberta Parente,Giuseppe Spadaro,Stefania Loffredo,Leonardo Cristinziano,Maria Rosaria Galdiero,Gilda Varricchi,Massimo Triggiani

doi:10.1007/s10238-021-00693-0

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.

Highlights

Mastocytosis is a rare clonal disorder characterized by uncontrolled proliferation, abnormal accumulation and survival of mast cells in several organs [1, 2]
We have previously reported that vascular endothelial growth factors (VEGFs)-A, VEGF-C, and VEGF-D can be detected by immunohistochemistry in human lung mast cells [66]
Serum concentrations of VEGF-A, VEGF-C, ANGPT1 and ANGPT2 are increased in patients with mastocytosis compared to healthy controls

Summary

Introduction

Mastocytosis is a rare clonal disorder characterized by uncontrolled proliferation, abnormal accumulation and survival of mast cells in several organs [1, 2] This pathological condition is due to a somatic activating mutations of KIT gene that encodes for tyrosine kinase receptor KIT (CD117) largely expressed on mast cells [3, 4]. More than 90% of patients with systemic mastocytosis have a gainof-function mutation in codon 816 of the receptor tyrosine kinase KIT, where a valine is substituted for an aspartate (KIT D816V) [5]. The symptoms of mastocytosis are the consequence of infiltration, activation and degranulation of MCs which exert local and systemic effects [10]

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