Introduction
Mastocytosis is a rare heterogeneous disease characterized by abnormal
proliferation and accumulation of mast cells (MCs) in different organs.
According to the World Health Organization (WHO) 2016 classification,
mastocytosis is classified as cutaneous mastocytosis, systemic
mastocytosis and mast cell sarcoma (1-3).
MCs are frequently found in perivascular area and lymphatic tissue,
release various mediators (4) during inflammation
which can cause vasodilatation by relaxing smooth muscle cells in the
vessels and activate the endothelial cells (ECs) leading to a breakdown
in tight junctions(4). Sustained activation of ECs can
cause endothelial dysfunction by increasing the vasoconstrictor
endothelial derived factors and reducing the vasodilator ones(5, 6) which have been reported in various systemic
diseases (7, 8).
Flow mediated dilation (FMD) as a gold standard noninvasive technique
measuring endothelial function by quantifying NO-dependent arterial
vasodilatation (9) is mostly used for clinical
research in cardiovascular diseases. It measures arterial flow mediated
changes as percentage dilatation of the brachial artery after short-term
occlusion (9, 10). Furthermore, endocan, Vascular
Endothelial Growth Factor (VEGF), endothelins (ETs) are some circulating
biomarkers used to evaluate endothelial function (8).
Endocan (also known as endothelial cell specific molecule-1) plays a
role in endothelial cytoskeleton rearrangement and inflammation and is
secreted from ECs (11). It is a modulator of VEGF
signaling whereas its expression is further induced by VEGF, revealing a
bidirectional interaction in between which plays a critical role in
inflammation (7). VEGF , an important growth factor in
promoting angiogenesis during embryogenesis (12) , can
increase during inflammation due to uncontrolled endothelial activation(13). ET-1, as a circulating aminopeptide in human
mainly produced by ECs, plays an important role in atherosclerosis which
can further cause vascular dysfunction (14-16). Tumor
necrosis factor alpha (TNF-α) and Interleukin-6 (IL-6) are inflammatory
biomarkers that can stimulate the release of ET-1. Furthermore, TNF-α
plays a role in atherosclerosis development (15) and
IL-6 can be a potential mediator of MCs activation and accumulation(17). High sensitive C-reactive protein (hsCRP) as a
marker of systemic inflammation has been shown to be associated with
increased risk of vascular pathologies (18).
Beside allergic inflammation, MCs can play an important role in
atherosclerotic lesions in human (19). Degranulation
of proinflammatory cytokines, histamine and neutral proteases, such as
tryptase from mast cells upon activation can lead to atherosclerotic
plaque progression, increasing plaque destabilization and risk of
intraplaque hemorrhage (20). The carotid intima media
thickness (CIMT) is measured between intra-luminal and the
medial-adventitial interfaces of the carotid artery by B-mode carotid
ultrasound to detect the presence and progression of atherosclerosis.
Increased CIMT is a predictor of future vascular atherosclerotic events(21, 22).
Although the effects of MCs on vascular structure and progression of
atherosclerosis are known, there are limited knowledge about endothelial
function in mastocytosis (5). Endothelial impairment
in mastocytosis has not been evaluated with biomarkers and its possible
relation with subclinical atherosclerosis has not been studied before.
In this study our aim was to investigate the endothelial function in
mastocytosis patients by FMD and related biomarkers and to assess the
presence of subclinical atherosclerosis by CIMT.