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.