Abstract
BackgroundDiabetic patients experience exaggerated intimal hyperplasia after endovascular procedures. Recently it has been shown that circulating smooth muscle progenitor cells (SPC) contribute to intimal hyperplasia. We hypothesized that SPC differentiation would be increased in diabetes and focused on modulation of TGF-β/BMP-6 signaling as potential underlying mechanism.MethodsWe isolated SPC from C57Bl/6 mice with streptozotocin-induced diabetes and controls. SPC differentiation was evaluated by immunofluorescent staining for αSMA and collagen Type I. SPC mRNA expression of TGF-β and BMP-6 was quantified using real-time PCR. Intima formation was assessed in cuffed femoral arteries. Homing of bone marrow derived cells to cuffed arterial segments was evaluated in animals transplanted with bone marrow from GFP-transgenic mice.ResultsWe observed that SPC differentiation was accelerated and numeric outgrowth increased in diabetic animals (24.6 ± 8.8 vs 8.3 ± 1.9 per HPF after 10 days, p < 0.05). Quantitative real-time PCR showed increased expression of TGF-β and decreased expression of the BMP-6 in diabetic SPC. SPC were MAC-3 positive, indicative of monocytic lineage. Intima formation in cuffed arterial segments was increased in diabetic mice (intima/media ratio 0.68 ± 0.15 vs 0.29 ± 0.06, p < 0.05). In GFP-chimeric mice, bone marrow derived cells were observed in the neointima (4.4 ± 3.3 cells per section) and particularly in the adventitia (43.6 ± 9.3 cells per section). GFP-positive cells were in part MAC-3 positive, but rarely expressed α-SMA.ConclusionsIn conclusion, in a diabetic mouse model, SPC levels are increased and SPC TGF-β/BMP-6 expression is modulated. Altered TGF-β/BMP-6 expression is known to regulate smooth muscle cell differentiation and may facilitate SPC differentiation. This may contribute to exaggerated intimal hyperplasia in diabetes as bone marrow derived cells home to sites of neointima formation.
Highlights
Diabetic patients experience exaggerated intimal hyperplasia after endovascular procedures
We hypothesized that inducing Type I diabetes in mice enhances smooth muscle progenitor cells (SPC) differentiation and numeric outgrowth with decreased BMP-6 expression and increased TGF-b expression in diabetic SPC
Intimal hyperplasia is exaggerated after cuff-induced vascular injury in diabetic mice We evaluated if the STZ-induced diabetic mice in our study displayed an exaggerated neointima formation as we expected
Summary
Diabetic patients experience exaggerated intimal hyperplasia after endovascular procedures. We hypothesized that SPC differentiation would be increased in diabetes and focused on modulation of TGF-b/BMP-6 signaling as potential underlying mechanism. Diabetic patients experience higher rates of restenosis due to intimal hyperplasia [1,2]. We have shown that in Type I diabetic patients, the outgrowth of cells with a smooth muscle/myofibroblast phenotype from cultured mononuclear cells was increased and that BMP-6 expression in these cells was down regulated [9]. We evaluated the effect of diabetes on TGF-b-expression in cultured SPC, as TGF-b is known to counteract BMP-6 signaling and enhance intimal hyperplasia. We hypothesized that inducing Type I diabetes in mice enhances SPC differentiation and numeric outgrowth with decreased BMP-6 expression and increased TGF-b expression in diabetic SPC
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