Abstract-Stimulation of collateral artery growth in patients has been hitherto unsuccessful, despite promising experimental approaches. Circulating monocytes are involved in the growth of collateral arteries, a process also referred to as arteriogenesis. Patients show a large heterogeneity in their natural arteriogenic response on arterial obstruction. We hypothesized that circulating cell transcriptomes would provide mechanistic insights and new therapeutic strategies to stimulate arteriogenesis. Collateral flow index was measured in 45 patients with single-vessel coronary artery disease, separating collateral responders (collateral flow index, Ͼ0.21) and nonresponders (collateral flow index, Յ0.21).Isolated monocytes were stimulated with lipopolysaccharide or taken into macrophage culture for 20 hours to mimic their phenotype during arteriogenesis. Genome-wide mRNA expression analysis revealed 244 differentially expressed genes (adjusted P, Ͻ0.05) in stimulated monocytes. Interferon (IFN)-␤ and several IFN-related genes showed increased mRNA levels in 3 of 4 cellular phenotypes from nonresponders. Macrophage gene expression correlated with stimulated monocytes, whereas resting monocytes and progenitor cells did not display differential gene regulation. In vitro, IFN-␤ dose-dependently inhibited smooth muscle cell proliferation. In a murine hindlimb model, perfusion measured 7 days after femoral artery ligation showed attenuated arteriogenesis in IFN-␤-treated mice compared with controls (treatment versus control: 31.5Ϯ1.2% versus 41.9Ϯ1.9% perfusion restoration, PϽ0.01). Key Words: collateral circulation Ⅲ arteriogenesis Ⅲ gene expression Ⅲ stress testing Ⅲ monocytes C ollateral artery growth, also termed arteriogenesis, is a natural escape mechanism in cases of arterial obstruction. 1 It alleviates symptoms of ischemia, and the extent of myocardial infarction is diminished if a sufficient collateral network is present. 2 Therefore, pharmacological stimulation of arteriogenesis is of potential benefit to a large number of patients.Despite the large body of evidence for the feasibility of pharmacological stimulation of arteriogenesis in various animal models, large randomized clinical trials have not demonstrated beneficial effects of a proarteriogenic treatment in patients. [3][4][5][6] Lack of knowledge on the molecular background of arteriogenesis in humans may explain the disappointing results of the clinical trials. Interestingly, a large heterogeneity exists in patients in their arteriogenic response on coronary obstruction. 7 Hence, comparative studies of patients responding with either sufficient or insufficient collateral artery growth can provide insights into arteriogenesis in humans and may reveal new therapeutic strategies.Circulating cells, especially monocytes and macrophages 8 but potentially also (endothelial) progenitor cells, 9 are involved in the arteriogenic remodeling process. In a previous study, we showed that CD44 expression is functionally involved in arteriogenesis in mice and is di...

Background— Granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently shown to increase collateral flow index in patients with coronary artery disease. Experimental models showed beneficial effects of GM-CSF on collateral artery growth in the peripheral circulation. Thus, in the present study, we evaluated the effects of GM-CSF in patients with peripheral artery disease. Methods and Results— A double-blinded, randomized, placebo-controlled study was performed in 40 patients with moderate or severe intermittent claudication. Patients were treated with placebo or subcutaneously applied GM-CSF (10 μg/kg) for a period of 14 days (total of 7 injections). GM-CSF treatment led to a strong increase in total white blood cell count and C-reactive protein. Monocyte fraction initially increased but thereafter decreased significantly as compared with baseline. Both the placebo group and the treatment group showed a significant increase in walking distance at day 14 (placebo: 127±67 versus 184±87 meters, P =0.03, GM-CSF: 126±66 versus 189±141 meters, P =0.04) and at day 90. Change in walking time, the primary end point of the study, was not different between groups. No change in ankle-brachial index was found on GM-CSF treatment at day 14 or at day 90. Laser Doppler flowmetry measurements showed a significant decrease in microcirculatory flow reserve in the control group ( P =0.03) and no change in the GM-CSF group. Conclusions— The present study does not support the use of GM-CSF for treatment of patients with moderate or severe intermittent claudication. Issues that need to be addressed are dosing, the selection of patients, and potential differences between GM-CSF effects in the coronary and the peripheral circulation.