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Imo E Hoefer

Publications and source records attributed to Imo E Hoefer.

15 recordsLinked to original sources
PubMed2007

End-stage renal disease causes an imbalance between endothelial and smooth muscle progenitor cells.

Patients with end-stage renal disease (ESRD) on hemodialysis have an increased risk of cardiovascular disease (CVD). Circulating endothelial progenitor cells (EPC) contribute to vascular regeneration and repair, thereby protecting against CVD. However, circulating smooth muscle progenitor cells (SPC) may contribute to adverse vascular remodeling. We hypothesized that an imbalance occurs between EPC and SPC in ESRD patients and sampled progenitor cells from 45 ESRD patients receiving regular treatment. Our study is the first to show reduced numbers of CD34+KDR+ hematopoietic stem cell (HSC)-derived EPC (type I EPC). Furthermore, monocyte-derived EPC cultured from mononuclear cells (type II EPC) were reduced in number and had a reduced capacity to stimulate endothelial cell angiogenesis. In contrast, SPC outgrowth was unaffected. In vitro incubation with uremic serum impaired type II EPC outgrowth from healthy donor mononuclear cells and did not influence SPC outgrowth. The hemodialysis procedure itself induced HSC apoptosis and caused an acute depletion of circulating EPC. Taken together, the decreased number and impaired function of EPC are compatible with impaired endogenous vascular repair in hemodialysis patients, whereas the unaffected SPC numbers suggest that the potential of progenitor cells to contribute to adverse remodeling is retained. This EPC-SPC imbalance may contribute to the acceleration of CVD in ESRD patients and could offer novel therapeutic targets.

Antigens, CD34↗
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

G-CSF administration after myocardial infarction in mice attenuates late ischemic cardiomyopathy by enhanced arteriogenesis.

Granulocyte-colony stimulating factor (G-CSF) has been shown to improve cardiac function after myocardial infarction (MI) by bone marrow cell mobilization and by protecting cardiomyocytes from apoptotic cell death. However, its role in collateral artery growth (arteriogenesis) has not been elucidated. Here, we investigated the effect of G-CSF on arteriolar growth and cardiac function in a murine MI model. Mice were treated with G-CSF (100 microg/kg/day) directly after MI for 5 consecutive days. G-CSF application resulted in a significant increase of circulating mononuclear cells expressing stem cell markers. Arterioles in the border zone of infarcted myocardium showed an increased expression of ICAM-1 accompanied by an accumulation of bone marrow derived cells and a pronounced proliferation of endothelial and smooth muscle cells. Histology of G-CSF treated mice revealed a lower amount of granulation tissue (67.8 vs. 84.4%) associated with a subsequent reduction in free LV wall thinning and scar extension (23.1 vs. 30.8% of LV). Furthermore, G-CSF treated animals showed a significant improvement of post-MI survival (68.8 vs. 46.2%). Pressure-volume relations revealed a partially restored myocardial function at day 30 (EF: 32.5 vs. 17.2%). Our results demonstrate that G-CSF administration after MI stimulates arteriogenesis and attenuates ischemic cardiomyopathy after MI.

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↗
PubMed2006

Pharmaceutical interventions to influence arteriogenesis: new concepts to treat ischemic heart disease.

Despite the technical progress in interventional techniques to overcome the harmful effects of ischemic heart disease there is still an urgent need for alternative, pharmaceutical treatment modalities. Exogenous stimulation of vessel growth, i.e. vasculogenesis, angiogenesis or arteriogenesis serves as a promising strategy to restore blood flow to the jeopardized tissue regions downstream of arterial stenosis or occlusion. While vasculogenesis is defined as the arrangement of angioblasts during prenatal development creating the first vascular network, angiogenesis and arteriogenesis refer to important adaptive mechanisms in the adult organism. Angiogenesis, neo-formation of capillaries, is a key process in many different physiological and pathophysiological events where improvement of microvascular function and tissue nutrition is needed (e.g. wound healing, tumor growth). In contrast to this capillary sprouting, the term arteriogenesis refers to the development of large caliber collateral arteries. Under conditions of increasing shear stress, anastomoses between interconnected perfusion territories can undergo adaptive enlargement, developing into a functional network of collateral arteries, natural bypasses able to maintain sufficient blood flow and compensating for the gradual occlusion of a large artery (e.g. in the coronary circulation). However, in most cases arteriogenesis does not proceed as fast as the stenosis progresses and infarction and tissue necrosis results. A well-developed collateral network is an important protective factor for the occurrence of ischemic events and therefore pharmaceutical acceleration and stimulation of arteriogenesis in patients represents an eminent aim for the future. This review focuses on the basic mechanisms of arteriogenesis, the recent progresses in translating these insights into the clinical situation and the problems yet to be solved.

Angiogenesis Inducing Agents↗
PubMed2005

Aspirin, but not clopidogrel, reduces collateral conductance in a rabbit model of femoral artery occlusion.

OBJECTIVES: The objective of this study was to test the potential of aspirin and clopidogrel to influence collateral artery growth (arteriogenesis). BACKGROUND: Aspirin and clopidogrel are antiplatelet agents commonly used in the treatment of ischemic cardiovascular disease. Both inhibit platelet aggregation; however, they differ mechanistically because aspirin acts via cyclooxygenase (COX) inhibition, while clopidogrel noncompetitively antagonizes the P2Y12 adenosine diphosphate receptor. We hypothesized that aspirin, due to its anti-inflammatory effects through inhibition of COX activity could inhibit arteriogenesis. Given that clopidogrel does not affect COX activity, it would be less likely to interfere with collateral artery growth. METHODS: Fifty-four New Zealand White rabbits received either saline, aspirin (10 mg/kg), or clopidogrel (10 mg/kg) for seven days after femoral artery ligation. Maximal collateral conductance was assessed with fluorescent microspheres under maximal vasodilation; cellular migration and proliferation (Ki-67) was evaluated by quantitative immunohistology. RESULTS: Collateral conductance was significantly reduced by aspirin treatment, whereas clopidogrel had a neutral effect (saline: 0.94 +/- 0.04; clopidogrel: 0.94 +/- 0.05; aspirin: 0.64 +/- 0.03 ml x min(-1) x 100 mm Hg(-1) x g(-1); p < 0.001). Ki-67 proliferation indexes were consistent with these results (saline: 23.1 +/- 2.9%; clopidogrel: 23.5 +/- 1.1%; aspirin: 19.2 +/- 1.1% Ki-67-positive cells). Immunohistochemistry showed COX expression in collateral arteries and a significantly decreased monocyte/macrophage accumulation in the perivascular tissue after aspirin treatment. Cell adhesion molecule expression on monocytes after activation was significantly reduced by aspirin, which might explain the reduced migratory ability. CONCLUSIONS: In summary, clopidogrel had a neutral effect on natural arteriogenesis. Aspirin significantly inhibited collateral artery growth, probably due to its anti-inflammatory effect. Additional studies are needed to substantiate these results before translation into clinical practice.

Animals↗
PubMed2005

Leukocyte subpopulations and arteriogenesis: specific role of monocytes, lymphocytes and granulocytes.

OBJECTIVE: Circulating leukocytes play a crucial role during arteriogenesis. However, known pro-arteriogenic compounds (MCP-1, GM-CSF) acting via monocytic pathways also exert positive effects on granulocytes and lymphocytes. The role of these two cell types in arteriogenesis remains yet to be clarified, which was the aim of the current study. METHODS: Ninety New Zealand White Rabbits received either phosphate buffered saline (PBS), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), neutrophil activating protein-2 (NAP-2) or lymphotactin (Ltn) via osmotic minipumps after unilateral femoral artery ligation. In vitro stimulation and in vivo assessment of chemoattraction confirmed cell-specific action of the compounds in rabbits. Arteriogenesis was evaluated by angiography and collateral conductance measurements using fluorescent microspheres. Quantitative immunohistology was used to quantify transmigrated leukocyte subtypes after infusion of the factors. RESULTS: MCP-1 infusion attracts monocytes and granulocytes, whereas IL-8 attracts all three cell types albeit monocytes to a significantly lower degree than MCP-1. NAP-2 and lymphotactin selectively attract granulocytes, respectively, lymphocytes. Of the tested cytokines, only MCP-1 stimulates arteriogenesis, as assessed by collateral conductance measurements ((ml/(min 100 mmHg)): PBS, 50.70+/-5.15; MCP-1, 216.30+/-12.30; IL-8, 58.91+/-5.56; NAP-2, 66.83+/-8.72; Ltn, 52.80+/-5.37) and angiographic findings. CONCLUSION: This study for the first time provides evidence that not granulocytes or T-lymphocytes but monocytes are the key mediators of arteriogenesis.

Animals↗
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↗
PubMed2004

Arteriogenesis proceeds via ICAM-1/Mac-1- mediated mechanisms.

Monocyte adhesion to shear stress-activated endothelium stands as an important initial step during arteriogenesis (collateral artery growth). Using multiple approaches, we tested the hypothesis that monocyte adhesion via intercellular adhesion molecule-1 (ICAM-1) and selectin interactions is essential for adaptive arteriogenesis. Forty-eight New Zealand White rabbits received either solvent, monocyte chemoattractant protein-1 (MCP-1) alone, MCP-1 plus ICAM-mab, or MCP-1 plus an IgG2a isotype control via osmotic minipumps. After 7 days, collateral conductance was evaluated: solvent 4.01 (mL/min per 100 mm Hg), MCP-1 plus ICAM-mab 8.04 (versus solvent P=NS), and MCP-1 alone 33.11 (versus solvent P<0.05). Furthermore, the right femoral arteries of ICAM-1-/-, Mac-1-/- and mice having defective selectin interactions (FT4/7-/-) as well as their corresponding controls were ligated. One week later, perfusion ratios were determined by the use of fluorescent microspheres. FT4/7-/- mice did not show any significant difference in perfusion restoration whereas ICAM-1-/- and Mac-1-/- mice had a significant reduction in arteriogenesis as compared with matching controls (FT4/7-WT 37+/-9%, FT4/7-/- 32+/-3%, P=0.31; C57BL/6J 59+/-9%, ICAM-1-/- 36+/-8%, P<0.05; Mac-1-/- 42+/-3%, P<0.05). ICAM-1/Mac-1-mediated monocyte adhesion to the endothelium of collateral arteries is an essential step for arteriogenesis, whereas this process can proceed via selectin interaction independent mechanisms. Furthermore, in vivo treatment with monoclonal antibodies against ICAM-1 totally abolishes the stimulatory effect of MCP-1 on collateral artery growth, suggesting that the mechanism of the MCP-1-induced arteriogenesis proceeds via the localization of monocytes rather than the action of the MCP-1 molecule itself.

Animals↗
PubMed2004

Abnormal monocyte recruitment and collateral artery formation in monocyte chemoattractant protein-1 deficient mice.

Monocyte chemoattractant protein 1 (MCP-1) has been shown to be effective for the stimulation of collateral artery formation in small and large animal models. The availability of a genetic knockout mouse enables evaluation of the importance of the role of MCP-1 in the natural course of collateral artery growth. In a total of 21 MCP-1 -/- as well as 13 of the appropriate genetic background controls ([129Sv/J X C57BI/6J]F1), a femoral artery ligation was performed. Subsequently, a polyethylene catheter, connected to an osmotic minipump, was inserted retrogradely into the occluded femoral artery with the tip pointing upstream. Using this technique, PBS (MCP-1 -/-: n = 13 and C57BI/6J: n = 13) or MCP-1 (JE; MCP-1 -/-: n = 8) was delivered intra-arterially. Seven days after ligation, determination of hind limb flow was assessed by controlled tissue perfusion using differently labeled fluorescent microspheres. MCP-1 -/- mice exhibited a reduction of hind limb flow of 32.9 +/- 9.2% of the unligated hind limb, compared with 55.4 +/- 6.8% in C57BI/6J mice (p<0.01). MCP-1 -/- mice that underwent a subsequent 'rescue' treatment with MCP-1 showed a restoration of flow to a level of 47.4 +/- 9.8% (p = NS compared with PBS-treated C57BI/6J). Specific immunohistochemical staining for monocytes (MOMA-2: MCP-1 -/-, n = 5 and C57BI/6J, n = 5) showed a reduced number of monocytes around developing collateral arteries in the MCP-1 -/- mice. In conclusion, our data show that the absence of MCP-1 causes a strong reduction in flow restoration after femoral artery occlusion, coinciding with a reduced monocyte attraction, emphasizing the central role of this chemokine in the multifactorial process of collateral artery formation.

Animals↗
PubMed2003

Involvement of the fibroblast growth factor system in adaptive and chemokine-induced arteriogenesis.

Fibroblast growth factors (FGFs) have been applied in a variety of therapeutic and experimental studies to improve collateral blood flow. However, the pathophysiological role and the temporospatial expression of the FGFs and their receptors during arteriogenesis have never been elucidated in vivo. Here, we report that collateral artery growth in its early phase is associated with an increased expression of FGF receptor-1 (FGFR-1) and syndecan-4 on mRNA and protein levels as well as with an increased kinase activity of FGFR-1 in a rabbit model of arteriogenesis. However, the mRNA levels of FGF-1 and -2 remained constant. Our data suggest that these growth factors are supplied by endothelial attracted monocytes that, in turn, produce and deliver the FGFs to growing collateral arteries. Monocyte chemoattractant protein-1-stimulated arteriogenesis was strongly reduced in rabbits by application of the FGF inhibitor polyanetholesulfonic acid, indicating that the monocyte-related arteriogenesis (as well as the unstimulated adaptation proper) is promoted by FGFs. In summary, this study shows that arteriogenesis is associated with an increased expression of the FGFRs at the site of the vessel, whereas the growth-promoting ligands are supplied by monocytes in a paracrine way.

Adaptation, Physiological↗
PubMed2003

Invasive and non-invasive evaluation of spontaneous arteriogenesis in a novel porcine model for peripheral arterial obstructive disease.

Our current knowledge regarding the efficacy of factors stimulating collateral artery growth in the peripheral circulation primarily stems from models in small animals. However, experimental models in large sized animals are a prerequisite for extrapolation of growth factor therapy to patients with peripheral atherosclerotic obstructive disease. Therefore, we have developed a novel porcine femoral artery ligation model using non-invasive and invasive evaluation techniques. In 12 young farm pigs and nine older minipigs, a ligation of the superficial femoral artery was performed. Using an intra-arterial catheter, phosphate buffered saline (PBS) was administered with a first-pass over the collateral vascular bed. Directly after ligation as well as after 2 weeks of continuous infusion of PBS, perfusion of the leg was measured using various flow and pressure parameters. Using a pump driven extracorporal system, collateral conductance was determined under maximal vasodilatation. Conductance decreased after acute ligation to similar levels in both young farm pigs as well as the older minipigs (both 9.3% of normal perfusion) and recovered after 2 weeks to a higher value in farm pigs compared with minipigs (22.4 vs. 12.7% of normal; P<0.05). Angiography using both X-ray and magnetic resonance imaging was performed to visualize the formed collateral arteries. To the best of our knowledge this is the first in vivo pig model for hemodynamic assessment of growth of collateral arteries in the peripheral circulation, that is suitable for evaluation of arteriogenic effects of growth factors or genes.

Angiography↗
PubMed2002

Modulation of collateral artery growth in a porcine hindlimb ligation model using MCP-1.

For an appropriate extrapolation to patients with peripheral arterial obstructive disease, we tested the efficacy of monocyte chemoattractant protein 1 (MCP-1) treatment in a porcine hindlimb ligation model. In 40 minipigs, a femoral artery ligation was performed. Control animals were examined immediately after ligation (n = 4) or after 2 wk of intra-arterial infusion of PBS (n = 11). A second group of animals was evaluated after intra-arterial infusion of 2.0 microg/h of MCP-1 for 48 h (followed by 12 days of PBS; n = 13) or 2 wk continuously (n = 12). In the terminal experiment after 2 wk, resting flow to the leg and peripheral arterial pressures were assessed without vasodilatation. Subsequently, vascular conductance was determined by using a pump-driven extracorporal circulation during maximal vasodilatation. The results showed that resting blood flow to the hindlimb was 53% of the normal after 2 wk of infusion of PBS, compared with 81% in both MCP-1 treatment groups (P < 0.05). Collateral conductance was 645 +/- 346 ml x min(-1) x mmHg(-1) after 2 wk of infusion with PBS, compared with 1,070 +/- 530 and 1,158 +/- 535 ml x min(-1) x mmHg(-1) after 48 h and 2 wk treatment with MCP-1, respectively (P < 0.05). Modulation of the process of arteriogenesis is feasible in this large animal model via intra-arterial infusion of the Cys-Cys-chemokine MCP-1.

Angiography↗
PubMed2002

Direct evidence for tumor necrosis factor-alpha signaling in arteriogenesis.

BACKGROUND: Arteriogenesis serves as an efficient mechanism for flow restoration after arterial occlusion. This process is associated with inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), although their role in arteriogenesis remains unclear. We hypothesized that arteriogenesis is reduced in mice lacking functional TNF-alpha or p55 receptor. To test this hypothesis, we developed a novel microsphere-based murine model of hindlimb perfusion measurement. METHODS AND RESULTS: Unilateral femoral arteries of nude (n=9), TNF-alpha(-/-) (n=9), TNF-alpha receptor p55(-/-) (n=8), and p75(-/-) (n=8) mice as well as their appropriate genetic background controls were occluded. The nude mice underwent laser Doppler hindlimb flux measurements preoperatively, postoperatively, and after 7 days. Seven days after ligation, all animals underwent tissue perfusion determinations using fluorescent microspheres. Laser Doppler findings confirmed acute decrease in flux with falsely normal values after 1 week. Microsphere results from control mice showed perfusion restoration to values approximately 50% of normal within 7 days. TNF-alpha(-/-) mice demonstrated a significant reduction (45.1%) in collateral artery perfusion compared with controls (TNF-alpha(-/-) 22.4+/-5.1% versus B6x129 49.7+/-9.3%; P<0.01). p55(-/-) mice exhibited an almost identical 45.8% reduction in collateral artery formation (p55(-/-) 28.3+/-4.3% versus C57BL/6J 61.8+/-9.1%; P<0.01), whereas p75(-/-) mice were equivalent to controls (p75(-/-) 54.5+/-5.5%; P=0.13). CONCLUSIONS: Microsphere techniques in mice offer a tool for the molecular dissection of arteriogenesis mechanisms. These results suggest that TNF-alpha positively modulates arteriogenesis probably via signaling through its p55 receptor.

Animals↗