Abstract
IntroductionPreviously, we demonstrated that children with active systemic vasculitis (SV) have higher circulating CD34 + CD133 + KDR+ endothelial progenitor cells (EPC); the function of these EPCs, and their relationship with disease activity in vasculitis remains largely unexplored. We hypothesized that although EPC numbers are higher, EPC function is impaired in active SV of the young. The aims of this study were therefore to: 1. investigate the relationship between disease activity and EPC function in children with SV; and 2. study the influence of systemic inflammation on EPC function by investigating the effects of hyperthermia and TNF-α on EPC function.MethodsWe performed a cross-sectional study of unselected children with SV with different levels of disease activity attending a single center (Great Ormond Street Hospital, London) between October 2008 and December 2014. EPCs were isolated from peripheral blood of children with SV, and healthy child controls. EPC function was assessed by their potential to form colonies (EPC-CFU), and ability to form clusters and incorporate into human umbilical vein endothelial cell (HUVEC) vascular structures in matrigel. The effects of hyperthermia and TNF-α on EPC function were also studied.ResultsTwenty children, median age 12-years (5–16.5; nine males) were studied. EPC-CFU and the number of EPC clusters formed on matrigel were significantly reduced in children with active vasculitis compared with healthy controls (p = 0.02 for EPC-CFU; p = 0.01 for EPC cluster formation). Those with active vasculitis had lower EPC-CFU and EPC cluster formation than those with inactive disease, although non-significantly so. In addition, EPC incorporation into matrigel HUVEC networks was lower in children with SV compared with healthy children, irrespective of disease activity. Ex-vivo pre-treatment of EPC with hyperthermia impaired EPC function; TNF-α down-regulated EPC expression of CD18/CD11b and resulted in decreased incorporation into HUVEC networks.ConclusionsWhilst our previous work showed that circulating CD34 + EPC numbers are well preserved, this study revealed that EPC function is significantly impaired in children with vasculitis. It is possible that the chronic inflammatory milieu associated with vasculitis may impair EPC function, and thus contribute to an unfavourable balance between endothelial injury and repair. The mechanism of this remains to be established, however.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0810-3) contains supplementary material, which is available to authorized users.
Highlights
We demonstrated that children with active systemic vasculitis (SV) have higher circulating CD34 + CD133 + KDR+ endothelial progenitor cells (EPC); the function of these EPCs, and their relationship with disease activity in vasculitis remains largely unexplored
Using in vitro assays recapitulating in vivo morphogenesis events we have shown that EPC adherence, colony formation, and integration into endothelial networks were significantly impaired in children with active SV compared to patients with inactive vasculitis and healthy child controls
Very little is currently known about EPC biology in patients with SV, studies suggest that chronic inflammatory autoimmune diseases including rheumatoid or psoriatic arthritis [36], systemic lupus erythematosus [6, 37], and systemic sclerosis [38] are associated with impairment in EPC function that could contribute to the excessive cardiovascular morbidity associated with these diseases
Summary
We demonstrated that children with active systemic vasculitis (SV) have higher circulating CD34 + CD133 + KDR+ endothelial progenitor cells (EPC); the function of these EPCs, and their relationship with disease activity in vasculitis remains largely unexplored. Endothelial activation and injury are central to the pathogenesis of SV with increased endothelial cell adhesion molecule expression, and a switch to a prothrombotic endothelial phenotype, both of which contribute to the vascular pathology of SV [3, 4] In addition to this severe endothelial injury, it has been suggested that endothelial repair processes may be impaired [5, 6], and SV could be damaging to the cardiovascular system due to an unfavourable imbalance between endothelial injury and repair, as is the case in other diseases targeting the endothelium [7, 8]. It is known that recruitment of bone marrowderived endothelial progenitor cells (EPC) represents an important mechanism of endothelial repair [9] These EPCs may play an important role in endothelial maintenance and vascular healing in health and disease, and. About the impact of SV on these repair processes, despite concerns that vascular dysfunction is an important late sequelae of vasculitis in children [13, 14] and adults [15]
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