Diabetes Mellitus And Arterial Hypertension Differentially Affect Macrophage Recruitment And Collateral Growth

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Further indication of the restriction of macrophage involvement to the early prolif-erative phase of collateral development and the physiological importance of the late remodeling phase came from experiments investigating the influence of different risk factors, namely the metabolic syndrom and arterial hypertension on collateral growth [64]. We investigated at which level two prominent risk factors, diabetes mellitus type II and arterial hypertension, impair collateral formation and assessed proliferative index (PI; BrdU infusion), macrophage accumulation (M0; ED 2 staining), collateral score (post-mortem angiography), collateral conductance (CC= collateral flow/pressure gradient; under maximal vasodilatation) and effect of MCP-1 treatment one week after femoral artery occlusion in normotensive Zucker Fatty Diabetic (ZDF) rats and control animals (ZDL rats). Results were compared with those of ZDF and ZDL rats rendered hypertensive via the Goldblatt method. While diabetic animals showed reduced collateral proliferation and macrophage accumulation hypertensive animals had reduced collateral conductances without altered macrophage accumulation and a smaller reduction in collateral proliferation. MCP-1 treatment only had significant pro-arteriogenic effects in diabetic but not in hypertensive animals. We concluded that diabetes mellitus impairs collateral proliferation via impaired monocyte/macrophage recruitment whereas arterial hypertension influences the later remodeling phase of collateral growth, which is unresponsive to increased monocyte recruitment. Only the enforcement of the remodeling phase in arterial hypertension but not the impairment of collateral proliferation and macrophage recruitment in diabetes mellitus had a profound influence on collateral conductance suggesting that the remodeling phase constitutes the rate limiting step with regard to collateral functionality. This was confirmed in experiments conducted by the group of Johannes Waltenberger. They had assessed the effect of VEGF A tretatment on perfusion ratio (Te-99m-MIBI nuclear scan) in autimmune diabetes in RIP-B7.1 C57BL/6 mice after preproinsulin DNA treatment (+ppIns). Although they were able to confirm that VEGF A treatment enhanced collateral perfusion and previously had shown that this effect is partly due to enhanced recruitment of monocytes/macrophages they did not see a difference of perfusion between diabetic and non-diabetic mice.

In this context it is interesting to note that shear force regulated remodeling of shunt vessels in the mesenteric artery model occurs in the absence of pronounced macrophage accumulation [46]. In this model shear force can be precisely regulated via occlusion of a defined range of mesenteric arch arteries. According to our current concept this model resembles the later remodeling phase of collateral growth that is independent of macrophage recruitment.


We thus far have seen that local activation of precursors cells either present at the time of occlusion or migrating into the collateral region during a very narrow time window after creation of a hemodynamically relevant stenosis (femoral artery occlusion) is of paramount importance for the initial proliferative phase of collateral growth. This activation appears to be hemodynamically triggered as all other stimuli (e.g. ischemia) are pretty much ruled out [41, 42]. In terms of therapeutical interventions it would be extremely interesting to be able to interfere with these mechanisms. This places mechanotransduction into the center of our attention. There are several theories more or less funded that try to explain the translation of mechanical signals into biochemical reactions and cellular responses. Certain genes are reported to have shear force response elements leading to their activation [49, 65]. It remains to be determined how these shear force response elements are mechanically activated. Other authors have focused their attention on ionchannels [66]. Again one needs to explain, how mechanical forces activate these ion channels.

The most appealing model today that is capable of explaining the interdependence of mechanical signals and biochemical responses as well as the integration and coordination of biochemical reactions across the cell is the "Tensegrity" model of Donald Ingber [67]. According to the "Tensegrity" model the whole cytoskeletal composition consisting of microtubules and intermediate filaments connected to focal adhesions containing various active proteins, cell adhesion molecules and integrins allows the transduction of mechanical forces into biochemical signals. At the same time it enables the integration of biochemical signals to elicit mechanical activities of the cell, like migration and cytokinesis [67].

One of the cell adhesion molecules the role of which had not been studied in collateral growth which however appeared to be closely related to endothelial cell migration and proliferation and co-localizes with avp3 integrin at the invasive front of the extravillous trophoblast was CEACAM1[68-70]. CEACAM1 is expressed on both endothelial cells and monocytes/macrophages. It has also has been shown to be expressed on vascular resident progenitor cells [36] (Figure 4a and 4b). CEACAM1 thus constitutes an interesting target for the explanation of the activation of vascular resident progenitor cells. In order to evaluate the in vivo impact of CEACAM1 on vascular growth and in particular on collateral growth, we used two different murine models: We generated CEACAM1endo+ mice on an FVB/N background with additional CEACAM1-L expression under the endothelial cell-specific promoter

Figure 4. The cell adhesion molecule CEACAM-1 is expressed on vascular resident progenitor cells and plays a significant role in collateral development. (a) Expression of CEACAM-1 on cells isolated from vascular resident progenitor cells sprouting from arteria mammaria segments. (B) Control staining. (c) Collateral blood flow is significantly higher in mice overexpressing CEACAM-1 in their endothelium. (d) Collateral blood flow is significantly lower in CEACAM-1 knock-out mic (A and B according to Zengin et al. Development, 133, 1543-1551; C and D according to Horst, Ito et al. J Clin Invest, 116, 1596-1596)

Figure 4. The cell adhesion molecule CEACAM-1 is expressed on vascular resident progenitor cells and plays a significant role in collateral development. (a) Expression of CEACAM-1 on cells isolated from vascular resident progenitor cells sprouting from arteria mammaria segments. (B) Control staining. (c) Collateral blood flow is significantly higher in mice overexpressing CEACAM-1 in their endothelium. (d) Collateral blood flow is significantly lower in CEACAM-1 knock-out mic (A and B according to Zengin et al. Development, 133, 1543-1551; C and D according to Horst, Ito et al. J Clin Invest, 116, 1596-1596)

control of the Tie2 receptor tyrosine kinase [7]. To observe the functional consequences of endothelial CEACAM1 deficiency, we also used Ceacam1~/- mice with systemic deletion of the Ceacam1-gen. For the CEACAM1endo+ transgenic line, we modified a construct by T.N. Sato. Transgenic founder lines were identified by Southern blotting, and two transgenic lines were used in the experiments described here. We also used two independent lines of the Ceacam1-/- mice in our experiments. Transgenic and knockout mice were genotyped by PCR (data not shown). To verify CEACAM1 over-expression in the endothelia of CEACAM1endo+ trans-genic animals, we double-labelled primary endothelial cells from lungs with anti-PECAM1- and anti-CEACAM1-antibodies in flow cytometry. We also confirmed CEACAM1 over-expression of endothelial cells in adult animals by Western blotting and RT-PCR. Macroscopically, no overt vascular damage or alterations were observed under physiological conditions in Ceacam1-/- or CEACAM1endo+ transgenic mice.

To validate a functional role for CEACAM1 in vascular remodeling in vivo, we investigated vascular growth after induction of ischemia via unilateral femoral artery occlusion in CEACAM1endo+ and Ceacam1-/- mice and their respective WT littermates. As functional parameter we determined collateral blood flows one week after femoral artery occlusion via fluorescent microspheres employing established methods of blood flow determination in mice [71]. Perfusion recovery in the ischemic leg was expressed in % of perfusion of the non-ligated leg as described previously [71]. We indeed were able to show that the relative perfusion of ischemic versus non-ischemic limbs 7 days after surgery was significantly higher in CEACAM1endo+ mice compared to their WT litter mates [7](Figure 4c and 4d). On the contrary perfusion in ischemic hindlimbs in Ceacam1-/- mice was significantly lower opposed to their genetically unaltered siblings. These findings indicated that CEACAM1 indeed plays a significant role during collateral growth. Our observation that increased collateral blood flows in CEACAM1endo+ mice are associated with an increase in the accumulation of inflammatory cells supports the notion that this cell adhesion plays an important role in the regulation of the activation of vascular resident precursor cells. Further support that this cell CECAM1 participates in collateral growth comes from experiments in which an increased CEACAMl-expression was observed after induction of myocardial ischemia [72].

Another target associated with the cytoskeleton and expressed in endothelial cells, smooth muscle cells and macrophages is the intermediate filament Vimentin [39](Figure 5). Its regulation during collateral growth was already described in dog collateral vessels [8]. In pilot experiments using 2-D gel electrophoresis and mass spectrometry to identify molecules involved in arteriogenesis we discovered that vimentin was upregulated in collateral vessels. In a parallel proteomic analysis of migrating and non-migrating endothelial cells we also identified vimentin as a major protein discriminating migrating from non-migrating endothelial cells [73]. Interestingly one of the proteins regulated in collateral arteries after increase of hemodynamic forces via shunt operations also was vimentin [56]. We subsequently performed siRNA assays, in which vimentin expression in migrating endothelial cells was suppressed to examine whether the intermediate filament has functional importance in cell migration [74]. We examined vimentin expression

Figure 5. Vimentin network (green fluorescence) and focal adhesions (red fluorescence) in vascular resident progenitor cells in transfected cells via Western blot and performed migration and proliferation assays. In the si vimentin samples the vimentin expression was barely detectable, pointing to a clear suppression of the target protein. Following the successful protein suppression, we examined potential functional concequences in endothelial cells. To this purpose, we performed migration assays with time lapse videomi-croscopy. The migration velocity of vimentin suppressed endothelial cells was significantly reduced compared to si-control transfected cells. The vimentin-siRNA transfected cells retained with 0.05 (±0.008) ^m/min only half the migration velocity of si-control transfected cells (0.1 (±0.01) ^m/min). The enormous reduction in migration speed of vimentin suppressed cells was also verified in the Boyden chamber - a more conservative migration assay. Thus, we were able to demonstrate a significant function of the intermediate filament vimentin in endothelial cell migration. However, the cytoskeleton plays a decisive role in many other cellular functions, including cell proliferation. Hence, we investigated if the suppression of vimentin expression also affects the proliferative activity of endothelial cells. After a 5.5 hour BrdU-incubation, 37 % of the si-control transfected cells stained BrdU positive. However, only 21 % of the si-vimentin trans-fected cells stained positive for BrdU. Hence, the diminished vimentin expression caused a reduction in proliferative activity of about 43 %. These results clearly indicated, that vimentin exerts a regulatory role in endothelial cell migration and proliferation. Given that the vasodilator-stimulating phosphoprotein (VASP) is a known adaptorprotein linking the system to signal transduction pathways, we stripped a Western blot after the detection of vimentin and analyzed the VASP phosphorylation state [75, 76]. The suppression of vimentin expression went hand in hand with a decrease of pSer239-VASP, whereas it had no influence on total VASP expression. Since the phosphorylation state of VASP regulates actin filament dynamics, we wanted to ensure that there are no side effects of vimentin suppression on actin expression which could be related to pSer239- VASP [76, 77]. Therefore, we determined actin expression in transfected cells and were able to show, that the suppression of vimentin does not alter actin expression. This excludes actin-dependent changes of pSer239-VASP expression as a possible side effect of vimentin suppression.

With regard to endothelial cell migration, our results suggest, that both proteins, Vimentin and VASP are dependently involved in this process. The migration of a cell is accomplished by lamellipodia protrusion via actin polymerization and attachment to the extracellular matrix. These actions must be reversible to allow cell motion [78, 79]. We hypothesize, that vimentin suppression leads to a diminished phosphorylation of VASP which in turn causes polymerization of actin filaments to form lamellipodia and filopodia. Because VASP is arrested in the unphospho-rylated state in cells with decreased vimentin expression, the cyclic depolymer-ization of actin filaments is inhibited, resulting in decelerated motility of the cell. In conclusion, our study demonstrates for the first time, that an intact vimentin network is essential for the migratory process in endothelial cells and, that it seems to function by regulating the VASP-actin interaction. Although we have demonstrated that Vimentin is involved in the transduction of biochemical signals into mechanical activities like migration and proliferation it remains to be determined whether this intermediate filament is also essential fort he transduction of mechanical signals into biochemical responses. Experiments perfomed by the groups of Jo de Mey and Daniel Henrion were able to demonstrate that Vimentin is essential for flow-mediated remodeling of arterial vessels [80]. These findings strongly suggest that Vimentin is not only important for inside-out but also outside-in mechanotransduction.


After having discussed the role of monocytes/macrophages and vascular resident precursor cells in collateral growth in extenso we might have generated more questions than answers- a strong indication that science is alive. However, in humbleness we may draw following preliminary conclusions:

The growth of collateral vessels is a complex process involving local as well as remote processes, a number of different cell types as well as altering hemodynamic and biochemical signals, proceeding in different phases [38, 81, 82]. During the past years several groups including ours have tried to define the different processes, phases, cell types and hemodynamic and biochemical signals. We have concentrated our research on hind-limb models because the anatomical structure of the hindlimb allows to study angiogenesis and the remodeling of preexisting arteriolar shunts into collateral arteries separately. As we started with a fairly simplified hypothesis mentioned in the introduction we had to learn that the process and the dynamics of the process are much more complex. Hemodynamic forces appear to alter in time and along the growing collateral vessel. At the same time there seems to be a profound influence of the vascularity of the ischemic down-stream region on the hemodynamic forces acting on the growing collateral vessel also termed "vascular backward signaling" [59]. This brings angiogenesis as a major albeit indirect contributor to the development of collateral vessels into focus again [82]. I have tried to summarize the different processes contributing to collateral vessel development and their interaction as we propose it now in a small cartoon that does not claim to be complete (Figure 6):

For the sake of simplicity the arterial circulation is drawn consisting of conductance and resistance vessels as well as the capillary bed. The whole process begins when the main blood supplying vessel is occluded or at least significantly stenosed (Top row second panel). Reduced blood flow in the periphery leads to increased resistance because blood viscosity depends on flow velocity and low flow leads to a procoagulant state favoring blood clot formation. Thus peripheral resistances rise dramatically upon occlusion of the main arterial supply resulting in

Figure 6. Schematic drawing of the different steps in collateral development and "key switches". Explanation in the text

decreased flow velocities in preexisting arteriolar shunts despite a rise in pressure gradients. Reduced flow velocities allow adhesion and migration of circulating cells (switch 1) into collateral vessels but also (not shown) into peripheral vessels and the capillary bed. Within a short time distal ischemia leads to peripheral vasodilatation (switch 3) increasing flow velocities and shear forces in preexisting arteriolar shunts thereby inhibiting further recruitment of circulating cells (switch 2). Instead, resident precursor cells, part of which originate from or are constantly replenished from the bone marrow, start to proliferate and differentiate into vascular cells and macrophages (switch 2, switch 4). This leads to primary outward remodeling of collateral vessels. At the same time angiogenesis is observed in the ischemic periphery (switch 5). After arterialization of this de-novo formed capillary bed (arteriogenesis in its narrow sence) new resistance vessels are formed resulting in a further decrease of peripheral resistances, which supposedly has a profound influence on the blood supplying collateral vessels (switch 7). At this stage of collateral development, however, hemodynamics appear to promote not only outward- but primarily inward remodeling processes, proliferation slows down considerably and the resulting cork-screw like distortions of collateral vessels impair full restoration of blood flow (switch 6).

As we still struggle to understand the basic physiology and cellular mechanisms of collateral vessel growth our understanding of the molecular mechanisms remains rudimentary [38, 82, 83]. Most models are still not differentiated enough to draw a conclusion at which level certain factors influence the growth of collateral vessels. For example, when looking at different studies there is no doubt that VEGF A has an impact on collateral growth but despite many investigations it remains an enigma, how this is achieved [14, 15, 71, 84] There is considerable reason to doubt that it is upregulated in the vicinity of growing collateral vessels [41]. The "arteriogenic" effect of VEGF A is NO dependent [71, 85]. Thus it is conceivable that the "arteriogenic" effect of this cytokines relies on its effect on peripheral vasodilatation leading to increased flow and shear forces in proliferating collateral vessels and thereby promoting their growth indirectly (switch 2). The same might be achieved by increasing peripheral vascularity via stimulating angiogenesis and later the differentiation of this vascular network into resistance vessels (switch 5 and 7) [83]. On the other hand one of the VEGF A receptors, FLT 1 has been shown to be present on monocytes and was shown to promote the recruitment of circulating cells [86, 87] and it has been shown that PlGF primarily signaling through FLT1 also promotes collateral growth [14]. Thus the therapeutic effect of VEGF homologues may also be explained by enhanced recruitment of circulating cells (switch 1). Further complexity is added by the fact that not all phases of collateral growth appear to be beneficial. Our investigations on the effect of diabetes mellitus and hypertension on collateral growth demonstrated that diabetes impairs the early proliferative phase of collateral growth (switch 4), whereas arterial hypertension appears to enforce the later remodeling phase of collateral growth (switch 6). Only arterial hypertension had a profound negative effect on collateral conductance in the rat hindlimb indicating that perhaps "negative" remodeling constitutes a rate limiting step in collateral vessel formation. The future task will be to define each switch on the molecular level. We have introduced two new candidates to an ever-growing list of possible molecular switches. Yet we cannot definitely say at the moment to which cellular respective physiological switch these molecular candidates belong. The "angiogenesis" switch is the best described at the moment (switch 5) [82, 83]. I will not go into further details because angiogenesis in its narrow meaning was never the focus of our research and is better described by others. There are some ideas how the primary network is transformed into an arterialized network and then is remodeled into arteriolar resistance vessels. The former process is called "arteriogenesis" in its narrow meaning whereas the last process remains nameless even for embryologists and is best described with the term "arterial remodeling" [83]. The same applies to the remodeling of arteriolar or even small arterial shunts into collateral arteries also called "arteriogenesis", which caused significant confusion [38]. The mechanisms of arterial remodeling have extensively been study in the context of diseased vessels with and without interventions like stent implantations [83]. It remains to be determined how "physiological" remodeling proceeds and what parts of pathological remodeling is "pathologic" and which parts belong to the physiological process. Numerous molecular candidates have been claimed to influence physiological remodeling of collateral arteries including NO, GMCSF, FGF family members, VEGF family members, TGF 6, TNF family members, PDGF BB and Angiopoeitins and Angiotensin[ 13, 38, 88-90]. They all remain only loosely connected, in theory are capable of perpetuating their influence on collateral growth through several of the above mentioned physiological switches and have not been tested extensively as to the locus of their influence. This certainly also applies to the molecular candidates we have identified.


Many would claim that this is an academic discussion of no use in terms of treating patients - good blood flow is good blood flow irrespective where it comes from. The problem is that the dynamics also appear to support reverse remodeling and short-term effects are easily counteracted as the physiological process proceeds. This applies particularly to our patients, who usually suffer from concomitant diseases like diabetes mellitus and arterial hypertension that profoundly influence vascular remodeling. Reverse remodeling of collateral vessels is exactly what appeared to have happened to all clinical trials conducted so far. They all generated sobering effects when it came to long-term success[91-94].

Meanwhile cell-based therapies have gained more and more interest und thus the involvement of circulating cells in collateral growth. Large clinical trials have claimed pronounced effects after injection of bone marrow derived cells in patients after myocardial infarction [95]. On closer observation these effects are rather negligible. The primary endpoint was improvement of ejection fraction measured by left ventricular angiography a method with a poor selectivity of up to ±10%. The difference between the treatment and the non-treatment group was in the order of 3% with a mild impairment over all. Trials using more sensitive methods like magnetic resonance tomography have only involved a limited number of patients but showed a similar improvement [96]. Notably these effects were achieved with minimal homing of the injected bone marrow derived cells supporting the notion that some paracrine activities of these cells are responsible for the improvement of left ventricular function and not the transformation of these cells into myocytes or vascular cells. Recently the Repair-AMI investigators claimed a significant effect on clinical outcome in patients receiving bone marrow derived cells after myocardial infarction. This however did not constitute the primary end point of the study and thus the study was not powered to prove clinical efficacy [97]. Other trials have generated conflicting results and were not able to detect a significant effect [98]. In contrast to what is claimed we are still far away from a decent therapeutical approach that makes use of collateral growth. Our investigations suggest that there is only a very narrow time window in which homing of circulating cells plays a role during collateral growth. Local activation of vascular resident progenitor cells appears to be much more important [9, 36]. Thus a therapeutical approach in which the activation and differentiation of these local cells is fostered appears to be much more rewarding. Yet the activation of these cells will only have a transient effect if we do not cope with the later remodeling of collateral vessels with its negative effect on collateral blood flow and conductance as we learned from our experiments with diabetic rats and mice. A successful therapy will take into account all the different steps of collateral growth. It likely will consist of the application of different substances targeting specific "switches" at defined time intervals perhaps as a locally targeted therapy. Merely one or two of these switches will regard monocytes/macrophages or vascular precursors because homing of circulating cells and activation of local vascular and inflammatory cells only constitute part of a cascade in which every step is of importance to generate a sustainable biological bypass circuit.


Yet another problem of designing a therapy enhancing collateral blood flow in patients suffering from occlusive vascular disease rests in the similarities of patho-physiological processes leading to atherosclerosis and the physiological process of collateral growth. This in particular pertains to macrophage accumulation. As they appear to play a major role during the initial phase of collateral growth they are also considered fundamental to plaque progression and plaque instability. Thus any therapy enhancing macrophage accumulation during collateral growth would automatically be accompanied by worsening of the underlying disease and increasing the danger of plaque rupture and thus further vessel occlusions. This phenomenon has been termed the "Janus phenomenon" in reference to the ancient roman god Janus who is always depicted with one head wearing two faces looking into opposite directions [99]. "Janus-like" implies having 2 contrasting aspects. A solution to this problem might come if one takes a close look at the two principle paradigms of the mechanism of atherosclerosis. Atherosclerosis certainly can be considered to be an inflammatory disease as pioneered in particular by Russel Ross and Peter Libby [100, 101]. Other researcher, however, put the focus not on this "response to injury" hypothesis but on the "response to retention" hypothesis [102]. According to this hypothesis the core problem of atherosclerosis is not the inflammatory process itself but the retention first of lipids and later of activated and dying inflammatory cells. These inflammatory cells are however part of the futile physiological attempt of the organism to cope with the increased burden of lipids in the diseased vessel wall (and perhaps the distorted vascular architecture).

This notion in fact is supported by several observations. Fist of all, despite several attempts no anti-inflammatory strategy has had any clinical success in fighting atherosclerosis. Instead we had to learn that certain anti-inflammatory drugs, in particular Cox 2 inhibitors might increase cardiovascular risk [103]. More importantly studies conducted already in the late 80ies had shown that large intravenous dosages of granulocyte macrophage stimulating factor (GMCSF) reduced the atherosclerotic burden in atherosclerotic Watanabe rabbits [104]. A recent study then elegantly delivered proof of the notion that healthy stimulated macrophages are capable of exiting the plaque and reduce atherosclerosis [37]. In this study Llodra et al studied congenic Ly5.1 and Ly5.2 C57BL 6 mice donors and recipients either as wild type or ApoE deficient mice, respectively, that can be distinguished by the singular difference in an allele for CD45 (Ly5) a pan-hematopoietic marker. After development of atherosclerosis in Ly 5.1 ApoE -/mice their aortas were transplanted either in athorsclerotic (ApoE -/-) or control Ly 5.2 mice. The authors were able to demonstrate a rapid regression of the athorscle-rotic burden of the transplanted aorta only in control Ly 5.2. mice but not in ApoE deficient Ly5.2 mice. This regression was associated with an emigration of Ly 5.1 positive macrophages from the transplanted atherosclerotic aorta into the regional lymphnodes of the Ly 5.2 positive recipient. Interestingly, only very little migration of Ly 5.2 positive macrophages into the atherosclerotic aorta was observed. Based upon their study and previously published investigations the authors propose that there is a continuous turn-over of macrophages in the vessel wall. Monocytes entering the vessel from the blood normally adopt a dendritic cell phenotype that is capable of emigrating from the vessel wall. In atherosclerosis this monocyte-dentritic cell transformation is blocked and the cells are inhibited in exiting the plaque. In additional in vitro studies the authors were able to show that e.g. the lipid mediators platelet activating factor (PAF) and lysophatidic acid (LPA) block the conversion of monocytes into migratory cells and favor their retention in the subadventitial space.

The observation that MCP-1 treatment lead to worsening of atherosclerosis in apo-E deficient mice does not necessarily contradict the notion that enhancement of the functional capacity of macrophages is capable of reducing atherosclerosis [105]. It only means that MCP-1 is not the right therapeutic target. MCP-1 obviously does not influence macrophage biology in a way that these cells are resistant to apoptosis and enabled to escape from the plaque. Instead more macrophages are drawn to the atherosclerotic lesion and transformation into migratory cells is blocked as with PAF and LPA.

Thus the problem is not that there is inflammation but that the inflammatory process remains incomplete. Macrophages in atherosclerotic disease are like a fleet of "old rotten garbage trucks" that when loaded with cholesterol are unable to move out off the vessel and instead pollute their surroundings and finally die. Instead of fighting inflammation in atherosclerotic disease one therefore should support a physiological inflammatory reaction. Hence, the "macrophage Janus" might loose his nasty side and look at you with a single smiling face. Based upon these thoughts one can develop the vision of a single therapeutic approach that enhances collateralization and reduces atherosclerosis by improving the functional capacity of macrophages and/or vascular resident progenitor cells.

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