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PRECLINICAL STUDY

Endothelial Progenitor Cells Participate in Nicotine-Mediated Angiogenesis

Christopher Heeschen, MD^_*,, Edwin Chang, PhD^_*, Alexandra Aicher, PhD and John P. Cooke, MD, PhD^_*,_*

^_* Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California
Molecular Cardiology, J.W. Goethe University, Frankfurt, Germany

Manuscript received February 24, 2006; revised manuscript received July 10, 2006, accepted July 24, 2006.

^_* Reprint requests and correspondence: Dr. John P. Cooke, Division of Cardiovascular Medicine, Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Drive, Stanford, California 94305. (Email: john.cooke{at}stanford.edu).

OBJECTIVES: We aimed to determine the role of endothelial progenitor cells (EPCs) in cholinergic angiogenesis.

BACKGROUND: Recently, we provided evidence for a new angiogenic pathway mediated by endothelial nicotinic acetylcholine receptors (nAChR). Increasing evidence suggests that circulating EPCs also contribute to postnatal neovascularization by homing to sites of neovascularization, a process termed postnatal vasculogenesis. Therefore, we investigated whether nAChR activation increases mobilization and/or recruitment of EPCs to a site of angiogenesis.

METHODS: To identify EPCs from reservoirs both inside and outside of the bone marrow and to avoid the adverse effects of total body irradiation, we employed a murine parabiosis model with tie-2-LacZ FvB/N mice connected to wild-type FvB/N mice and induced unilateral hind limb ischemia in the wild-type animal.

RESULTS: Administration of nicotine increased capillary density in the ischemic hind limb, and increased soluble Kit ligand plasma levels. The effect of systemic administration was greater than that of local delivery of nicotine (45% vs. 76% increase in capillary density by comparison to vehicle control, intramuscular vs. oral administration of nicotine; p < 0.05). Ischemia-induced incorporation of EPC in the control group was rare, but was increased 5-fold by systemic administration of nicotine. Exposure to nicotine in vitro increased EPC count and EPC transmigration. Finally, systemic administration of nicotine increased EPC number in the bone marrow and spleen during hind limb ischemia.

CONCLUSIONS: Nicotine treatment increased the number of EPCs in the bone marrow and spleen, and increased their incorporation into the vasculature of ischemic tissue. Administration of nicotine increased markers of EPC mobilization. This study indicates that the known angiogenic effect of nicotine may be mediated in part by mobilization of precursor cells.

Abbreviations and Acronyms   DMXB = 3-(2,4)-dimethoxybenzylidene anabaseine   EPC = endothelial progenitor cell   FITC = fluorescein isothiocyanate   HUVEC = human umbilical vein endothelial cell   nAChR = nicotinic acetylcholine receptor   SDF = stem cell-derived factor   VEGF = vascular endothelial growth factor

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