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.
Highlights
Stem cell transplantation (SCT) is an important treatment for several malignant disorders including leukemia and solid tumors, as well as for non-malignant conditions such as metabolic and genetic diseases
Animal and heart weights The but not significantly different (Bu-Cy) treated mice had a significant reduction in the body weight compared to control group (Table 1)
A conditioning regimen is a prerequisite for a successful transplantation and different conditioning regimens have been utilized
Summary
Stem cell transplantation (SCT) is an important treatment for several malignant disorders including leukemia and solid tumors, as well as for non-malignant conditions such as metabolic and genetic diseases. Despite a continuous improvement of SCT, several complications such as sinusoidal obstructive syndrome (SOS), graft versus host disease (GVHD), cardiac toxicity and treatment-related mortality are still major limiting factors. These factors are important in the determination of long term outcomes f SCT [4]. The mechanisms underlying these complications have not been fully clarified Several factors such as the conditioning regimen, infections and alterations in the immune system have been recently addressed and related to late cardiovascular problems [11,12]. Injury to the vascular system may lead to fatal organ dysfunction involving the cardiovascular [9,13] or respiratory systems [14]
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