Busulphan-Cyclophosphamide Cause Endothelial Injury, Remodeling of Resistance Arteries and Enhanced Expression of Endothelial Nitric Oxide Synthase

Abstract

Stem cell transplantation (SCT) is a curative treatment for malignant and non malignant diseases. However, transplantation-related complications including cardiovascular disease deteriorate the clinical outcome and quality of life. We have investigated the acute effects of conditioning regimen on the pharmacology, physiology and structure of large elastic arteries and small resistance-sized arteries in a SCT mouse model. Mesenteric resistance arteries and aorta were dissected from Balb/c mice conditioned with busulphan (Bu) and cyclophosphamide (Cy). In vitro isometric force development and pharmacology, in combination with RT-PCR, Western blotting and electron microscopy were used to study vascular properties. Compared with controls, mesenteric resistance arteries from the Bu-Cy group had larger internal circumference, showed enhanced endothelium mediated relaxation and increased expression of endothelial nitric oxide synthase (eNOS). Bu-Cy treated animals had lower mean blood pressure and signs of endothelial injury. Aortas of treated animals had a higher reactivity to noradrenaline. We conclude that short-term consequences of Bu-Cy treatment divergently affect large and small arteries of the cardiovascular system. The increased noradrenaline reactivity of large elastic arteries was not associated with increased blood pressure at rest. Instead, Bu-Cy treatment lowered blood pressure via augmented microvascular endothelial dependent relaxation, increased expression of vascular eNOS and remodeling toward a larger lumen. The changes in the properties of resistance arteries can be associated with direct effects of the compounds on vascular wall or possibly indirectly induced via altered translational activity associated with the reduced hematocrit and shear stress. This study contributes to understanding the mechanisms that underlie the early effects of conditioning regimen on resistance arteries and may help in designing further investigations to understand the late effects on vascular system.

Conditioned Medium from Human Tonsil-Derived Mesenchymal Stem Cells Enhances Bone Marrow Engraftment via Endothelial Cell Restoration by Pleiotrophin

“…It was shown that PTN expressed from BM perivascular stromal cells plays a role in homeostatic hematopoiesis, while vascular ECs secreted PTN under BM ablation. Even though endogenous PTN can regulate hematopoiesis under injury, BM preconditioning involves damage to niche compartments including ECs, as indicated by increased levels of circulating ECs [25]. Therefore, supplementation of MSC CM and/or recombinant PTN may accelerate restoration of BM function.…”

“…Endothelia play important roles in maintaining vascular homeostasis, and intercellular junctions support structural integrity and cell-to-cell communication. High-dose chemotherapy causes significant damage to the endothelium [24,25], and delayed recovery of endothelial integrity may result in defects to vascular function. Regarding HSCT, elevated levels of circulating ECs indicate endothelial damage as well as graft-versus-host disease [41].…”

“…Increased ECs in circulation is an indicator of EC injury after treatment with cytotoxic drugs like Bu and Cy [24,25]. In order to determine if BMT and CM treatment could restore the injured ECs, we examined circulating EC levels (CD45 -CD144 + ) using flow cytometry on day 4 post-BMT.…”

Spectrum of Complement-Mediated Thrombotic Microangiopathies: Pathogenetic Insights Identifying Novel Treatment Approaches

“…203 Diagnosing TMA in the setting of BMT/SCT is challenging because thrombocytopenia, renal insufficiency, and the presence of schistocytes may also represent other complications, such as graft versus host disease (GvHD) and systemic infections. 141,204 Endothelial cell injury, induced by chemotherapy 205 and cyclosporine, 184 a prothrombotic state 206 and additional risk factors such as intravenous catheters, infections, and GvHD may well contribute to TMA pathogenesis. 203 In addition, endothelial cell regeneration is limited, as bone marrow endothelial progenitor cell populations, the source for endothelial cell repair, are depleted by the conditioning treatments.…”

Hematopoietic stem cell transplant effects on the kidney: Endothelial view

“…In ex vivo studies of arteries and arterioles exposed to common conditioning agents, busulfan, and cyclophosphamide, morphologic analysis revealed detachment of ECs from the basement membrane and disruption of endothelial cell–cell contact. 18 As with radiation, immediate enhanced vascular relaxation correlated with detected upregulation of eNOS that was hypothesized to be a marker of endothelial stress, although the exact mechanism remains unclear. Cyclosporin A and tacrolimus are the two calcineurin inhibitors (CNIs) that are widely used for treatment and prophylaxis of GVHD and are well known for their kidney and vascular toxicity brought on by constriction and hyperplasia of small arteries resulting in renal blood flow and glomerular filtration rate reduction.…”