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Biomedical subjects

Marco M Jost

Publications and source records attributed to Marco M Jost.

6 recordsLinked to original sources
PubMed2006

Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice.

It has been suggested that monocytes/macrophages represent the pivotal cell type during early adaptive growth of pre-existent arterial anastomoses toward functional collateral arteries (arteriogenesis) upon arterial occlusion. This hypothesis was supported by previous studies providing evidence that elevation of the peripheral monocyte count, increased monocyte survival (e.g., granulocyte macrophage-colony stimulating factor), as well as enhanced attraction or adhesion (e.g., monocyte chemoattractant protein 1; intercellular adhesion molecule 1) of the latter cells correlates directly with the arteriogenic response to restore tissue perfusion. However, the experimental proof of the essential role of monocytes/macrophages remains to be given. We therefore hypothesized that arteriogenesis is reduced in a genuine, nonpharmocologically induced monocyte/macrophage-deficient model of femoral artery occlusion in osteopetrotic (op/op) mice. Total leukocyte count did not differ between op/op mice and control (B6C3Fe a/a-Csf1(+/+)) mice. op/op mice show a significant monocytopenia (0.67%+/-0.38% vs. 1.53%+/-0.32%), granulocytosis (33.66%+/-6.67% vs. 22.83+/-7.47%), and a concomitant, relative lymphopenia (65.67%+/-6.58% vs. 75.65%+/-7.31%). Microsphere-based perfusion measurement 7 days after femoral artery occlusion demonstrated a significantly reduced perfusion restoration upon femoral artery occlusion in op/op mice as compared with controls (28.19%+/-0.91% vs. 47.88%+/-2.49%). The application of a novel method of high resolution (microfocus X-ray system) angiography revealed a reduction of proliferation and diameter of collateral arteries. Quantitative immunohistology showed significantly lower numbers of macrophages in the surrounding tissue of proliferating arteries. This study provides additional evidence for the preeminent role of monocytes/macrophages during arteriogenesis in a genuine model of monocyte deficiency, i.e., without pharmacological intervention.

Animals↗
PubMed2006

Experimental models of arteriogenesis: differences and implications.

Cardiovascular and cerebrovascular disease represent the two most common causes of mortality and morbidity in western countries, and the treatment for these is generally by the mechanical restoration of blood flow in the affected tissues. Stimulation of collateral artery growth (arteriogenesis) provides a potential alternative option for the treatment of patients suffering from occlusive artery disease. Therefore, researchers have established several angiogenesis and arteriogenesis animal models to investigate basic mechanisms and pharmacological modulation of collateral artery growth. The authors highlight the most important aspects of vascular growth, discuss different methods and techniques for examining the process, and review the advantages and disadvantages associated with the animal models available for studying this phenomenon.

Angiography↗
PubMed2005

The concept of functional peptidomics for the discovery of bioactive peptides in cell culture models.

Detection and purification of novel bioactive peptides from biological sources is a scientific task that led to a substantial number of important discoveries. One major laborious approach used is the repetitive stepwise separation of the test sample into several fractions followed by the determination of their bioactivity, until purity allows for sequence identification. We tested whether functional peptidomics, a combination of biological read-outs with differential peptide display (DPD) is a suitable strategy to isolate bioactive peptides at lower workload and with improved success. Additionally, we evaluated the use of DPD to monitor the processing status of proinsulin by inhibition of the insulin processing pathway. The rat insulinoma cell line INS-1 stimulated either with 2 mmol/l or 10 mmol/l glucose was used as model to generate differential peptide displays. In parallel, the bioactivity of the supernatants from the INS-1 cells was measured by glucose uptake and lipolysis assays using the adipocyte cell line 3T3-L1. We were able to quickly and elegantly trace the known activity of insulin to increase glucose uptake and inhibit lipolysis. Following re-chromatography of selected fractions, relevant peptides were identified by DPD and bioassays: the rat insulin-1 precursor and two different insulin peptides. We demonstrated in a semi-quantitative fashion that inhibition of proinsulin processing leads to accumulation of the insulin precursor, and reduced secretion of insulin-1. Thus, we conclude that DPD is an attractive support technology in peptide purification strategies aiming to identify bioactive compounds, and is superior to ELISA in discriminating between the processing status of insulin and its precursor.

Adult↗
PubMed2004

Differential effects of MCP-1 and leptin on collateral flow and arteriogenesis.

OBJECTIVE: Strategies to therapeutically stimulate collateral artery growth in experimental models have been studied intensively in the last decades. However, the experimental methods to detect collateral artery growth are discussed controversially and vary significantly. We compared different methods in a model of arteriogenesis in the rabbit hind limb and determined the effects on collateral flow of a known pro-arteriogenic factor, monocyte chemoattractant protein-1 (MCP-1), and a cytokine not previously evaluated for its arteriogenic efficacy, the adipocytokine leptin. METHODS AND RESULTS: Forty-two New Zealand White rabbits received either MCP-1, leptin or PBS after ligation of the right femoral artery. The pro-arteriogenic effect of MCP-1 was confirmed by flow measurements during reactive hyperemia, as demonstrated by increased flow ratio (PBS 0.56+/-0.07 vs. MCP-1 0.77+/-0.06, no unit, p<0.0001), ankle-brachial index and microsphere-based conductance measurements (PBS 50.8+/-2.1 vs. MCP-1 225.8+/-8.8 ml/min/100 mm Hg, p<0.001). Biological activity of leptin on rabbit monocytes was shown by a dose dependent increase in Mac-1 expression. In-vivo administration of leptin also led to an increase in hyperemic flow and flow ratio (leptin 0.69+/-0.03, p<0.05 vs. PBS), but not to an increase in collateral conductance (leptin 54.7+/-4.1 ml/min/100 mm Hg, p=ns vs. PBS) or proliferation of vascular smooth muscle cells (Ki-67 staining: PBS 24.7+/-3.9%, leptin 22.7%+/-0.8% (p=ns), MCP-1 32.0+/-1.9% (p<0.01)). Ki-67 mRNA measured by real-time polymerase chain reaction increased (8.8+/-3.1-fold, p<0.01) during natural arteriogenesis, and was further enhanced (25.5+/-8.1-fold, p<0.005) after stimulation with MCP-1. CONCLUSION: MCP-1 and leptin increase collateral flow in the rabbit hind limb model. In contrast to MCP-1, leptin does not enhance direct markers of vascular proliferation such as collateral conductance under maximal vasodilation and proliferation indices. The observed increase in hyperemic collateral flow thus most probably can be attributed to the well-documented vasodilatory effects of leptin. These data stress the necessity of the use of proliferation markers and microsphere-based conductance measurements under maximal vasodilation in order to separate effects of substances on vascular proliferation from effects on vasodilation.

Animals↗
PubMed2003

Divergent effects of GM-CSF and TGFbeta1 on bone marrow-derived macrophage arginase-1 activity, MCP-1 expression, and matrix metalloproteinase-12: a potential role during arteriogenesis.

Granulocyte/macrophage-colony stimulating factor (GM-CSF) and transforming growth factor (TGF)beta1 induce arteriogenesis in a nonischemic model of femoral artery ligation. Moreover, clinical trials demonstrated an improved collateralization after injection of bone marrow cells. In the present study, the expression of arteriogenic factors in bone marrow-derived macrophages (BMDM) was measured to verify the potential of these cells to influence collateral artery growth. GM-CSF induced in BMDM the expression of monocyte chemoattractive protein (MCP)-1, matrix-metalloproteinase (MMP)-12, and arginase-1-the latter also showing a remarkable increase in activity. During in vivo induced arteriogenesis, the accumulation rate of macrophages around proliferating collaterals was significantly increased. We also show that MCP-1 is found to be mainly expressed in the media of the vessel wall, MMP-12 in macrophages of the adventitia, and arginase at both locations. This study provides for the first time a comprehensive analysis of GM-CSF/TGFbeta1-regulated arteriogenic factors in BMDM and supports the hypothesis that arteriogenesis is a multistage mechanism, including monocyte/macrophage adhesion and transmigration, pro-arteriogenic cytokine expression, degradation of connective tissue, and collagen synthesis regulation. Selective modulation of these mechanisms as well as cell-based therapies supplying arteriogenic factors in vivo point toward new strategies to influence collateral artery growth.

Animals↗