Modulation of TGF-β/BMP-6 expression and increased levels of circulating smooth muscle progenitor cells in a type I diabetes mouse model
Open Access
- 21 September 2010
- journal article
- Published by Springer Science and Business Media LLC in Cardiovascular Diabetology
- Vol. 9 (1), 55
- https://doi.org/10.1186/1475-2840-9-55
Abstract
Background Diabetic 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. Methods We 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. Results We 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. Conclusions In 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.Keywords
This publication has 36 references indexed in Scilit:
- Cilostazol inhibits high glucose- and angiotensin II-induced type 1 plasminogen activator inhibitor expression in artery wall and neointimal region after vascular injuryAtherosclerosis, 2009
- The phosphodiesterase‐5 inhibitor vardenafil improves cardiovascular dysfunction in experimental diabetes mellitusBritish Journal of Pharmacology, 2009
- A new rat model of diabetic macrovascular complicationCardiovascular Research, 2007
- The Effect of Stem Cell Mobilization by Granulocyte-Colony Stimulating Factor on Neointimal Hyperplasia and Endothelial Healing After Vascular Injury With Bare-Metal Versus Paclitaxel-Eluting StentsJournal of the American College of Cardiology, 2006
- Vascular Neointimal Formation and Signaling Pathway Activation in Response to Stent Injury in Insulin-Resistant and Diabetic AnimalsCirculation Research, 2005
- Validation of internal control genes for gene expression analysis in diabetic glomerulosclerosisKidney International, 2004
- Smooth Muscle Progenitor Cells in Vascular DiseaseTrends in Cardiovascular Medicine, 2004
- Induction of Bone Morphogenetic Protein-6 in Skin Wounds. Delayed Reepitheliazation and Scar Formation in BMP-6 Overexpressing Transgenic MiceJournal of Investigative Dermatology, 1998
- Overexpression of bone morphogenetic protein-6 (BMP-6) in the epidermis of transgenic mice: inhibition or stimulation of proliferation depending on the pattern of transgene expression and formation of psoriatic lesions.The Journal of cell biology, 1996
- Recombinant Vgr-1/BMP-6-expressing tumors induce fibrosis and endochondral bone formation in vivo.The Journal of cell biology, 1994