Endothelial Progenitor Cells Participate in Nicotine-Mediated Angiogenesis
Why the study?
The role of endothelial progenitor cells in cholinergic angiogenesis mediated by nicotinic acetylcholine receptors was unclear.
Does nicotine administration increase the mobilization and recruitment of endothelial progenitor cells to sites of angiogenesis in a murine model of hind limb ischemia?
Key Points
- Determine the role of endothelial progenitor cells in cholinergic angiogenesis and evaluate whether nicotinic acetylcholine receptor activation promotes their mobilization and recruitment to ischemic sites.
- Utilized a murine parabiosis model joining tie-2-LacZ FvB/N mice to wild-type FvB/N mice to avoid total body irradiation.
- Induced unilateral hind limb ischemia in the wild-type partner and administered nicotine either locally (intramuscular) or systemically (oral) alongside vehicle controls.
- Conducted in vitro assays to measure endothelial progenitor cell counts and transmigration.
- Systemic nicotine enhanced capillary density in ischemic limbs more than local delivery (76% vs. 45% increase compared to vehicle control; p < 0.05) and raised soluble Kit ligand plasma levels.
- Systemic nicotine caused a 5-fold increase in the incorporation of endothelial progenitor cells into ischemic vasculature relative to vehicle control.
- Nicotine treatment increased endothelial progenitor cell counts in bone marrow and spleen during ischemia, as well as increasing in vitro progenitor cell proliferation and transmigration.
Structured PICO
Does nicotine administration increase the mobilization and recruitment of endothelial progenitor cells to sites of angiogenesis in a murine model of hind limb ischemia?
P
Population
Murine parabiosis model with induced unilateral hind limb ischemia to study the effects of nicotine on endothelial progenitor cells.
I
Intervention
Nicotine administration (systemic oral vs. local intramuscular) and in vitro exposure
C
Comparator
Vehicle control
O
Outcome
Capillary density, EPC mobilization and incorporation into ischemic tissuesurrogate
Main Result
p-value: p=<0.05
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Nicotine can be good or it can be bad. It can be therapeutic or pathological. In this article we focused on the pathological aspects. We report that nicotine accelerates tumor growth, because it enhances the tumor's proliferation of new blood vessels — angiogenesis.”
“We expected to see that nicotine impairs angiogenesis because it's known that smoking impairs endothelial function. But nicotine is not smoking.”
Implication
Nicotine promotes angiogenesis in ischemic tissue in part by mobilizing endothelial progenitor cells from the bone marrow and spleen.
Abstract
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.
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Cite This Study
Heeschen et al. (2006) studied Hind limb ischemia. Nicotine vs. Vehicle control was evaluated on Capillary density (p=<0.05).