Busulphan-cyclophosphamide cause endothelial injury, remodeling of resistance arteries and enhanced expression of endothelial nitric oxide synthase

• Published in: PloS one Vol. 7; no. 1; p. e30897
• Main Authors: Al-Hashmi, Sulaiman, Boels, Piet J M, Zadjali, Fahad, Sadeghi, Behnam, Sällström, Johan, Hultenby, Kjell, Hassan, Zuzana, Arner, Anders, Hassan, Moustapha
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 27.01.2012; Public Library of Science (PLoS)
• Subjects: Acetylcholine - pharmacology; Acute effects; Animals; Aorta; Aorta - drug effects; Aorta - enzymology; Aorta - pathology; Aorta - physiopathology; Arteries; Biology; Biomechanical Phenomena - drug effects; Blood; Blood pressure; Blood Pressure - drug effects; Body Weight - drug effects; Busulfan; Busulfan - adverse effects; Cancer therapies; Cardiovascular diseases; Cardiovascular system; Chemotherapy; Colforsin - pharmacology; Complications; Conditioning; Cyclophosphamide; Cyclophosphamide - adverse effects; Drug dosages; Electron microscopy; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - pathology; Endothelium, Vascular - physiopathology; Female; Hematocrit; Hypertension; Immune system; In Vitro Techniques; Isometric; Laboratories; Mechanical stimuli; Medical research; Medical treatment; Medicin och hälsovetenskap; Medicine; Mesenteric Arteries - drug effects; Mesenteric Arteries - enzymology; Mesenteric Arteries - pathology; Mesenteric Arteries - physiopathology; Mice; Mice, Inbred BALB C; Microvasculature; Mortality; Myocardium - enzymology; Myocardium - pathology; Myocardium - ultrastructure; Nitric oxide; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Nitroprusside - pharmacology; Noradrenaline; Norepinephrine; Norepinephrine - pharmacology; Organ Size - drug effects; Pharmacology; Physiological aspects; Physiology; Polymerase chain reaction; Quality of life; Remodeling; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Shear stress; Stem cell transplantation; Stem cells; Transplantation; Transplants & implants; Vascular Resistance - drug effects; Vascular system; Vasoconstriction - drug effects; Vasodilation - drug effects; Veins & arteries; Western blotting; Sweden
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0030897

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.