Troidl K.,Goethe University Frankfurt |
Troidl K.,Max Planck Institute For Herz Und Lungenforschung |
Jung G.,Goethe University Frankfurt |
Jung G.,Max Planck Institute For Herz Und Lungenforschung |
And 6 more authors.
Gefasschirurgie | Year: 2011
The fluid shear stress (FSS)-induced remodeling of pre-existing collateral arterioles into functional conducting arteries is termed arteriogenesis. This process can partially compensate for blood supply after occlusion of a main artery. A therapeutic aim in patients with arterial occlusive disease is to stimulate the growth of collateral vessels. MicroRNAs (miRNA) are small non-coding RNAs, which regulate gene expression by specific binding to mRNAs. Stress signals can influence the miRNA profile, which in turn might serve as mediators transmiting the physical stimulus into a cellular response. In the present study we provide a miR-NA signature of growing collaterals after FSS stimulation. A previously identified cardiac specific miR-24 could be localized in blood vessels. By combining fluorescent in situ hybridization with immunostaining the localization could be further specified in endothelial and smooth muscle cells. Since the therapeutic modulation of miRNAs is critical in cardiovascular cells, we have developed a catheter-based method to locally modulate specific miRNAs in mouse collateral vessels. Investigating the arteriogenic response after miRNA modulation allows the identification of miRNA-triggered signal transduction pathways during arteriogenesis. The proposed local delivery of miRNA modulating substances provides promising new therapeutic approaches. © Springer-Verlag 2011.
Troidl C.,Franz Groedel Institute |
Jung G.,Max Planck Institute for Heart and Lung Research |
Jung G.,Goethe University Frankfurt |
Troidl K.,Max Planck Institute for Heart and Lung Research |
And 8 more authors.
Current Vascular Pharmacology | Year: 2013
Chronic arterial occlusion leads to growth of collaterals - a process termed arteriogenesis, in which macrophages play a prominent role in remodelling and growth. However, a detailed analysis which of distinct macrophage subpopulations involved in arteriogenesis has never been performed. In the present study the temporal and spatial distribution of macrophage subtypes during arteriogenesis in a rat model with chronically elevated fluid shear stress (FSS) is investigated. Local macrophage subpopulations were histologically immuno-phenotyped using CD68 (a ubiquitous macrophage marker) and CD163, a specific M2 macrophage marker. Without occlusion few M2-macrophages reside in the perivascular space. Early after occlusion (12h) the number of M2 macrophages increases strongly and M1 macrophages begin emerging into the collateral. After 3 days they appear in the perivascular space. Both macrophage subtypes increase until 28d after treatment, whereas M2 macrophages dominate at the site of collateral growth. The local distribution of the subpopulations changes during the arteriogenic process. Whereas M1 macrophages are detected directly adjacent to the media, M2 macrophages are present in the most outer perivascular region of the growing collateral vessel. Systemic alterations of blood leucocytes in mice after femoral artery ligature (FAL) were investigated by FACS analysis of serial blood samples. During collateral remodelling histological changes were not reflected in circulating monocytes in the peripheral blood. The activation state of macrophages in mice with FAL was modulated by injections of either dexamethasone or the interleukins IL10 or IL3/IL14. The arteriogenic response was assessed by hind limb perfusion with laser Doppler measurements after 3, 7 and 14d. Suppressing inflammatory monocyte subtypes (M1) with dexamethasone led to impaired perfusion recovery after FAL in mice, whereas IL10 or IL4/IL13 application significantly increased perfusion recovery. This investigation demonstrates that a forced shift towards M2 macrophages improves the arteriogenic response. The distinct early increase and spatial distribution of M2 macrophages support the idea that this subtype plays a predominant role during collateral remodelling. © 2013 Bentham Science Publishers.
Szardien S.,Kerckhoff Heart Center |
Szardien S.,Franz Groedel Institute |
Nef H.M.,Kerckhoff Heart Center |
Nef H.M.,Franz Groedel Institute |
And 19 more authors.
International Journal of Molecular Medicine | Year: 2012
The paradigm that cardiac myocytes are non-proliferating, terminally differentiated cells was recently challenged by studies reporting the ability of bone marrow-derived cells (BMCs) to differentiate into cardiomyocytes after myocardial damage. However, little knowledge exists about the role of BMCs in the heart during physiological aging. Twelve-week-old mice (n=36) were sublethally irradiated and bone marrow from littermates transgenic for enhanced green fluorescent protein (eGFP) was transplanted. After 4 weeks, 18 mice were sacrificed at the age of 4 months and served as controls (group A); the remaining mice were sacrificed at the age of 18 months (group B). Group A did not exhibit a significant number of eGFP + cells, whereas 9.4±2.8 eGFP + cells/mm 2 was documented in group B. In total, only five eGFP + cardio myocytes were detected in 20 examined hearts, excluding a functional role of BM differentiation in cardiomyocytes. Similarly, a relevant differentiation of BMCs in endothelial or smooth muscle cells was excluded. In contrast, numerous BM-derived fibroblasts and myofibroblasts were observed in group B, but none were detected in group A. The present study demonstrates that BMCs transdifferentiate into fibroblasts and myofibroblasts in the aging murine myocardium, suggesting their contribution to the preservation of the structural integrity of the myocardium, while they do not account for regenerative processes of the heart.