Endothelial Dysfunction and Altered Mechanical and Structural Properties of Resistance Arteries in a Murine Model of Graft-versus-Host Disease

Abstract

A putative involvement of the vasculature seems to play a critical role in the pathophysiology of graft-versus-host disease (GVHD). We aimed to characterize alterations of mesenteric resistance arteries in GVHD in a fully MHC-mismatched model of BALB/c mice conditioned with total body irradiation that underwent transplantation with bone marrow cells and splenocytes from syngeneic (BALB/c) or allogeneic (C57BL/6) donors. After 4 weeks, animals were sacrificed and mesenteric resistance arteries were studied in a pressurized myograph. The expression of endothelial (eNOS) and inducible nitric oxide (NO)-synthase (iNOS) was quantified and vessel wall ultrastructure was investigated with electron microscopy. The myograph study revealed an endothelial dysfunction in allogeneic-transplant recipients, whereas endothelium-independent vasodilation was similar to syngeneic-transplant recipients or untreated controls. The expression of eNOS was decreased and iNOS increased, possibly contributing to endothelial dysfunction. Additionally, arteries of allogeneic transplant recipients exhibited a geometry-independent increase in vessels strain. For both findings, electron microscopy provided a structural correlate by showing severe damage of the whole vessel wall in allogeneic-transplant recipient animals. Our study provides further data to prove, and is the first to characterize, functional and structural vascular alterations in the early course after allogeneic transplantation directly in an ex vivo setting and, therefore, strongly supports the hypothesis of a vascular form of GVHD.

Endothelial microparticles delivering microRNA-155 into T lymphocytes are involved in the initiation of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

“…However, the detailed pathomechanism underlying the initiation of aGVHD remains poorly understood. Recently, some evidences postulated that endothelial damage played an important role in the initiation of aGVHD [3, 4]. Number of circulating endothelial cells increases during the early phases of conditioning regimens, suggesting that chemotherapeutic drugs induce endothelial damage to release endogenous “danger signals” [5].…”

Venous thromboembolism following hematopoietic stem cell transplantation—a systematic review and meta-analysis

“…The role of donor T cells post-allogeneic-HSCT adhering to endothelium in the vasculature as the first potential extensive area of contact with new host antigens is well established [37,38]. For chronic GVHD which exhibits a unique pathogenesis distinct from acute GVHD [39], current evidence indicates that, in addition to damage to targeted epithelia, changes to the microvascular endothelium play a role in the pathogenesis of chronic GVHD [40][41][42]. It is well known that long-term survivors after allogeneic-HSCT are at a high risk for premature arterial vascular disease [43][44][45].…”

Pathophysiology of GvHD and Other HSCT-Related Major Complications

“…Murine models have demonstrated the role of endothelial neovascularization induced by conditioning leading to GvHD (91–93) and infiltrating donor T cells. Recently, Schmid et al showed for the first time in a murine system that not only endothelial venules but also arterial vessels suffer direct endothelial damage during GvHD (94). Detailed studies in patients have shown an association of loss of dermal vessels, with CD8+ T cell infiltrates, demonstrating allogeneic reactions against endothelial cells (95, 96).…”