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ANESTHETIC PHARMACOLOGY

Stem Cell-Like Human Endothelial Progenitors Show Enhanced Colony-Forming Capacity After Brief Sevoflurane Exposure: Preconditioning of Angiogenic Cells by Volatile Anesthetics

Eliana Lucchinetti, PhD^*, Steffen M. Zeisberger, PhD, Isabella Baruscotti, MS, Johannes Wacker, MD, Jianhua Feng, MD, PhD^*, Kathrin Zaugg, MD, PhD^||, Raghvendra Dubey, PhD, Andreas H. Zisch, PhD, and Michael Zaugg, MD^¶#

From the *Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Alberta, Canada; Department of Obstetrics and Gynecology, University Hospital Zurich; Department of Obstetrics and Gynecology, Clinics for Reproductive Endocrinology, University Hospital Zurich; Institute of Anesthesiology, University Hospital Zurich; ||Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland; ¶Department of Anesthesiology and Pain Medicine, University of Alberta; and #Perioperative Translational Medicine, Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada.

Address correspondence and reprint requests to Michael Zaugg, MD, DEAA, FRCPC, Department of Anesthesiology and Pain Medicine, University of Alberta, 8-120 Clinical Sciences Building, Edmonton Alberta, Canada T6G 2G3. Address e-mail to michael. zaugg{at}ualberta.ca.

BACKGROUND: Endothelial progenitor cells play a pivotal role in tissue repair, and thus are used for cell replacement therapies in "regenerative medicine." We tested whether the anesthetic sevoflurane would modulate growth or mobilization of these angiogenic cells.

METHODS: In an in vitro model, mononuclear cells isolated from peripheral blood of healthy donors were preconditioned with sevoflurane (3 times 30 min at 2 vol% interspersed by 30 min of air). Colony-forming units were determined after 9 days in culture and compared with time-matched untreated control. Using magnetic cell sorting, CD133+/CD34+ endothelial progenitors were enriched from human umbilical cord blood, and vascular endothelial growth factor (VEGF), VEGFR2 (KDR), granulocyte colony-stimulating factor (G-CSF), STAT3, c-kit, and CXCR4 expressions were determined in sevoflurane-treated and untreated cells by real-time reverse transcriptase polymerase chain reaction. In a volunteer study with crossover design, we tested whether sevoflurane inhalation (<1 vol% end-tidal concentration) would mobilize endothelial progenitor cells from the bone marrow niche into the circulation using flow cytometry of peripheral blood samples. VEGF and G-CSF plasma levels were also measured.

RESULTS: In vitro sevoflurane exposure of mononuclear cells enhanced colony-forming capacity and increased VEGF mRNA levels in CD133+/CD34+ cord blood cells (P = 0.017). Sevoflurane inhalation in healthy volunteers did not alter the number of CD133+/CD34+ or KDR+/CD34+ endothelial progenitors in the circulation, but increased the number of colony-forming units (P = 0.034), whereas VEGF and G-CSF plasma levels remained unchanged.

CONCLUSIONS: Sevoflurane preconditioning promotes growth and proliferation of stem cell-like human endothelial progenitors. Hence, it may be used to promote perioperative vascular healing and to support cell replacement therapies.