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Cardiovascular Research Advance Access originally published online on February 5, 2008
Cardiovascular Research 2008 78(2):242-249; doi:10.1093/cvr/cvn027
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Post-ischaemic neovascularization and inflammation

Jean-Sebastien Silvestre*, Ziad Mallat, Alain Tedgui and Bernard I. Lévy

Cardiovascular Research Center, Inserm Lariboisiere, Inserm U689, Universite Paris 7, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris cedex 10, France

* Corresponding author. Tel: +33 153216702; fax: +33 142813128. E-mail address: jean-sebastien.silvestre{at}larib.inserm.fr

Received 18 September 2007; revised 11 January 2008; accepted 30 January 2008

Time for primary review: 22 days


   Abstract
Top
 Abstract
1. Introduction
 2. Inflammation and hypoxia...
 3. Inflammation and mechanical...
 4. Inflammation and progenitor...
 5. Type of inflammatory...
 6. Conclusions
 Funding
 References
 
Four principal processes—vasculogenesis, angiogenesis, arteriogenesis, and collateral growth—characterize tissue repair and remodelling in acute and chronic ischaemic vascular diseases. The relative importance of each process remains unclear, but it is likely that they may complement each other. In addition, these processes are driven by distinct, but partially overlapping, cellular and molecular pathways. In particular, inflammation might be one of the most important stimuli for initiation of vessel growth in the setting of ischaemia. Here, we summarize the current knowledge on the inflammatory response in the context of ischaemia and review the major factors that may be involved in inflammation-induced, post-ischaemic neovascularization.

KEYWORDS Inflammation; Ischaemia; Angiogenesis; Arteriogenesis


   1. Introduction
Top
 Abstract
 1. Introduction
2. Inflammation and hypoxia...
 3. Inflammation and mechanical...
 4. Inflammation and progenitor...
 5. Type of inflammatory...
 6. Conclusions
 Funding
 References
 
There are four different forms of vascular growth: vasculogenesis refers to the formation of blood vessels by endothelial progenitors; angiogenesis and arteriogenesis refer to the sprouting and subsequent stabilization of these sprouts by mural cells; and collateral growth denotes the expansive growth of pre-existing vessels, forming collateral bridges between arterial networks.1

During embryogenesis, the vascular system emerges first from vasculogenesis in which endothelial cell precursors differentiate into endothelial cells to form a primitive capillary network. The subsequent growth and expansion of these primitive vessels into a capillary network is referred to as angiogenesis. The nascent vessels are then stabilized by recruiting mural cells and generation of an extracellular matrix, a process termed arteriogenesis. The vascular network then reaches a high level of organization by maturation, both at the level of the vessel wall and at the network level. The origin, number, type, and organization of mural cells and the composition of the associated matrix depend on the location and the function of the vessel, but also on the microenvironmental cue. In particular, the development of collateral vessels participates in the maturation of the vascular network. This collateral growth is characterized by enlargement of small pre-existing anastomoses towards large conductance arteries and is driven by changes in luminal shear stress.

Neovascularization also occurs in the adult during pathological conditions such as tumour growth or ischaemic diseases. The four principal processes, vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, contribute to tissue repair and remodelling during acute and chronic ischaemic vascular diseases, and represent the final targets of therapeutic neovascularization aimed at providing an alternative treatment strategy for patients with lower limb ischaemia and coronary artery disease. It should be noted that some groups have assimilated collateral growth in the setting of ischaemia to post-natal arteriogenesis and both terms are used as well.2

The relative importance of each of these processes remains unclear.1 Nevertheless, considering collateral growth, arteriogenesis, angiogenesis, and vasculogenesis as distinct processes occurring in different tissues is oversimplification. It is clear that collateral growth, arteriogenesis, and angiogenesis are parts of the same process in the succession of events leading to neovascularization. It is likely that they may complement each other: collateral growth and arteriogenesis provide bulk flow to the tissue but the rise in capillary density (i.e. angiogenesis) is probably required to salvage the ischaemic region. Angiogenesis and collateral growth are driven by distinct, but partially overlapping, cellular and molecular pathways. Hypoxia is known to trigger angiogenesis in the setting of ischaemia, whereas fluid shear stress (FSS) might be the most important stimulus for initiation of collateral growth. Besides these specific initial triggers, angiogenesis and collateral growth share growth factors, chemokines, proteases, and inflammatory cells, which play different roles in promoting and refining these processes. The presence of inflammatory cells is a prominent feature of post-ischaemic revascularization. This review focuses on the role of inflammation in vessel growth after vascular occlusion.


   2. Inflammation and hypoxia-dependent vessel growth
Top
 Abstract
 1. Introduction
 2. Inflammation and hypoxia...
3. Inflammation and mechanical...
 4. Inflammation and progenitor...
 5. Type of inflammatory...
 6. Conclusions
 Funding
 References
 
A major driving force for post-ischaemic vessel growth is hypoxia within the surrounding tissue. The main mechanism of hypoxia-induced angiogenesis involves the rise in hypoxia-inducible factor (HIF) proteins. There are two alternative oxygen regulated HIF-subunits, HIF-1 and HIF-2, which exhibit evidence of differential sensitivity to oxygen, differential expression in different cell types, and selective activation of at least some target genes.3 In addition, HIF-1 is a heterodimeric protein containing two subunits, HIF-1{alpha} and β, which bind to specific hypoxia-responsive element in the regulatory regions of several hypoxia-sensitive genes, such as vascular endothelial growth factor (VEGF)-A.4

Hypoxia controls the inflammatory reaction. Activation of HIF-1{alpha} is essential for myeloid cell infiltration and activation in vivo through a mechanism independent of VEGF. HIF-1{alpha} is crucial for the regulation of glycolytic capacity in myeloid cells: when HIF-1{alpha} is absent, the cellular ATP pool is drastically reduced. The metabolic defect results in profound impairment of myeloid cell aggregation, motility, and invasiveness.5 Hypoxia also represses activation-induced cell death by TCR/CD3 stimulation, resulting in an increased survival of the cells. Microarray analysis suggested the involvement of HIF-1 target gene product adrenomedullin in this process.6 In addition, hypoxia has been shown to modulate the adhesion capacity of inflammatory cells. Exposure of the promonocytic cell line U937 to hypoxia resulted in increased adhesion to activated endothelial cells. Such increases are transcription-dependent and are blocked by antibodies directed against murine β2 integrin. Subsequent studies identified a binding site for HIF-1 in the CD18 gene. HIF-1 binding has been demonstrated in vivo, and mutational analysis of the HIF-1 site within the CD18 promoter resulted in a loss of hypoxia-dependent inducibility.7

Alternatively, inflammatory cytokines may control HIF-1 dependent signalling. IL-1β strongly increases HIF-1{alpha} activity in cultured human hepatoma cells, emphasizing a possible role of HIF-1{alpha} as a trans-acting factor in inflammatory process as well.8 TGFβ markedly and specifically decreases both mRNA and protein levels of a HIF-1{alpha} -associated prolyl hydroxylase (PHD), PHD2, through the Smad signalling pathway. As a consequence, the degradation of HIF-1{alpha} is inhibited as determined by impaired degradation of a reporter protein containing the HIF-1{alpha} oxygen-dependent degradation domain encompassing the PHD-targeted prolines.9 It should also be noted that hypoxia can activate gene transcription in macrophages by mechanisms that are independent of HIF. For example, hypoxia increases macrophage intracellular levels of hydrogen peroxide, which is associated with increased binding of the transcription factor AP-1 to the CXCL-8 promoter and concurrent increase in the pro-angiogenic CXCL8 mRNA expression.10,11


   3. Inflammation and mechanical stress-dependent vessel growth
Top
 Abstract
 1. Introduction
 2. Inflammation and hypoxia...
 3. Inflammation and mechanical...
4. Inflammation and progenitor...
 5. Type of inflammatory...
 6. Conclusions
 Funding
 References
 
Physical forces generated within the collateral arterioles after an increase of blood flow are also major triggers of vessel growth. The rise in blood flow results from the difference in pressure between the pre-existing arterioles connecting upstream from the point of occlusion and those downstream. Physical forces such as elevated FSS activate vessel wall remodelling. Chronically increasing FSS by draining the collateral flow directly into the venous system using a side-to-side anastomosis between the distal stump of the occluded femoral artery and the accompanying vein has been shown to overcome the anatomical restrictions of collateral arteries and is potentially able to completely restore maximal collateral conductance.12 Increased FSS activates the Ras-ERK-, the Rho-, and the NO- (but not the Akt-) pathway enabling collateral artery growth.12,13 The primary physiological response to FSS is an activation of endothelial cells, and a large number of genes are controlled by shear stress responsive elements in their promoter.14 Of interest, increased FSS results in increased production of endothelial adhesion molecules, chemokines, and chemokine receptors. Chemotactic proteins called chemokines regulate accumulation of leukocytes at inflammatory sites. Four major chemokine subfamilies are distinguished based on the arrangement of conserved cystein residues within the amino acid sequences. Chemokines are potent mediators of cell adhesion and migration through their interactions with a family of G-protein-coupled receptors (CCR, CXCR or CX3CR) expressed on leukocytes. The most extensively studied chemokine contributing to post-ischaemic neovascularization is the monocyte chemoattractant protein-1 (MCP-1). MCP-1 upregulated at the site of collateral growth is markedly enhanced with MCP-1 treatment.15 Similarly, mice lacking the MCP-1 receptor CCR2 show a significant decrease in active foot movement score and enhanced gastrocnemius muscle atrophy. Morphometric analysis also shows a lesser increase in collateral vessel diameters in CCR2-deficient mice.16 Transgenic mice expressing the mouse JE-MCP-1 gene under the control of the {alpha}-cardiac myosin heavy chain promoter have reduced infarct area and scar formation and improved left ventricle function after myocardial infarction. These mice also show induction of macrophage infiltration and neovascularization.17 Of interest, monoclonal antibodies directed against ICAM-1 hamper neovascularization, suggesting that ICAM-1/Mac-1-mediated monocyte adhesion to the endothelium of collateral arteries is an essential step for collateral growth. Furthermore, in vivo treatment with monoclonal antibodies against ICAM-1 totally abolishes the stimulatory effect of MCP-1 on collateral artery growth. Therefore, the mechanism of MCP-1-induced arteriogenesis proceeds via attraction and localization of monocytes rather than through a direct arteriogenic effect of MCP-1 itself.18 Surprisingly, results concerning MCP-1- and CCR2-deficient mice have been variable. Some reports demonstrate similar capillary density and tissue perfusion in mice lacking MCP-1 or CCR2.19,20 The surgical procedure used to induce ischaemia, the type of tissue, and the existence of compensatory mechanisms, such as upregulation of MCP-1 in CCR2-deficient mice, may account for these discrepancies.21

In addition, a large array of chemokines can also affect leukocyte recruitment and thereby influence collateral growth and the response to tissue ischaemia. In this view, CXCL-9 and -10, through their interaction with their receptor CXCR3, may also modulate post-ischaemic vessel growth. Ischaemia induced by femoral artery ligature improves the number of CXCR3-expressing cells and the level of its ligands, CXCL-9 and -10. Angiographic score, blood flow recovery measurement, and capillary density analysis show a significant decrease of ischaemic/non-ischaemic leg ratio in CXCR3-deficient mice. This effect is associated with a marked reduction in macrophages and CD3+ lymphocyte infiltration.22

Tissue ischaemia also rapidly stimulates mRNA expression of fractalkine. Fractalkine induces new vessel formation on the excised rat aorta and chick chorioallantoic membrane through upregulation of HIF-1{alpha} resulting from CX3CR1. In vivo fractalkine-induced angiogenesis is completely blocked by functional inhibition of VEGF receptor 2 (KDR) and Rho GTPase. The condition of rat hindlimb ischaemia was significantly alleviated by the injection of whole-length fractalkine protein.23 In addition, loss of CX3CR1 function delays wound closure in both CX3CR1-knockout mice and in wild-type mice infused with anti-CX3CR1-neutralizing antibody. Conversely, transfer of bone marrow from donor wild-type mice, but not from donor CX3CR1 KO mice, restores wound healing to normal in CX3CR1 KO-recipient mice. Direct effects of CX3CR1 disruption at the wound site included marked reduction of macrophages and macrophage products, such as TGF-β1 and VEGF-A. Consistent with this, neovascularization is markedly reduced.24

After left hindlimb ischaemia, the ischaemic/normal limb paw perfusion ratio and capillary density are persistently lower in P-selectin-deficient mice compared with wild-type mice. The number of infiltrated leukocytes expressing VEGF-A is also decreased in P-selectin-deficient mice, suggesting that P-selectin may play an important role in ischaemia-induced neovascularization by promoting early inflammatory mononuclear cell infiltration.25

Finally, FSS may also enhance synthesis of pro-inflammatory molecules. Direct myocardial mechanical stretch associated with myocardial infarction, maximal in the infarct and peri-infarct zone, can promote myocardial production of pro-inflammatory cytokines such as TNF{alpha} and IL-6 in the myocardium.26 A mechanical stimulus acts through potential mechanosensors (integrins, cytoskeleton, and sarcolemmal proteins) and triggers major intracellular cross-talking signal transduction pathways, mitogen-activated protein kinase, JAK-signal transducer and activator of transcription (STAT), and calcineurin-dependent pathways. These pathways activate cognate downstream nuclear transcription factors, such as NF{kappa}B and AP-1, which are required for the induction of most cytokine genes, including TNF{alpha} and IL-6.27


   4. Inflammation and progenitor cell-dependent vessel growth
Top
 Abstract
 1. Introduction
 2. Inflammation and hypoxia...
 3. Inflammation and mechanical...
 4. Inflammation and progenitor...
5. Type of inflammatory...
 6. Conclusions
 Funding
 References
 
Recent studies indicate that post-natal neovascularization does not rely exclusively on angiogenesis and collateral growth, but also involves bone marrow-derived circulating endothelial progenitor cells (EPC). A specific subset of endothelial cell precursor was shown to home and incorporate into the site of neovascularization within the ischaemic tissue where differentiation into endothelial cells is completed. However, the relative contribution of circulating EPC to adult organ and tumour vasculature is highly variable and may range from a minor28–30 to a major contribution.31 Several factors may have contributed to these large differences in numbers, including EPC responses to the microenvironmental cue, the experimental animal models and the method of progenitor cells isolation. In particular, the gradient of hypoxia, which directs EPC to coalesce into independent vascular structures within the ischaemic region, may be an important determinant of variability. Indeed, the extent of incorporation is directly proportional to the degree of tissue ischaemia.32 This may likely explain the lack of incorporation of bone marrow-derived cells into vascular structures of the normoxic calf muscle as reported in some experimental models of hindlimb ischaemia.29 In addition, bone marrow-derived EPC appear to be a heterogeneous group of cells originating from multiple precursors and present in different stages of endothelial differentiation in peripheral blood. Finally, non-bone marrow-derived c-kit(+)CD45(–) progenitors have also been shown to contribute to post-natal neovascularization to an extent that is similar to that of bone marrow-derived progenitor cells.33

Nevertheless, increasing evidence indicates that some populations of progenitor cells do not promote vascular growth by incorporating into vessel walls but may function as supporting cells to deliver growth factors to pathological tissues and contribute to neovascularization and tissue/vessel remodelling through paracrine effects.34–36 In this view, bone marrow-derived progenitor cells accumulate around growing collateral arteries. These cells are identified as fibroblasts, pericytes, and primarily leukocytes that stain positive for several growth factors and chemokines.29 Hematopoietic cytokines, through graded deployment of SDF-1 from platelets, support mobilization and recruitment of CXCR4+ VEGFR1+ progenitor cells around vascular structures, which subsequently promote collateral growth.37 Similarly, VEGF is sufficient for organ homing of circulating mononuclear myeloid cells and is required for their perivascular positioning and retention through activation of SDF-1 signalling.38 Progenitors from human peripheral blood have been shown to differentiate into both early and late EPC. Early EPC express monocytic lineage markers, display spindle shape, show peak growth at 2 to 3 weeks and die at 4 weeks.36,39 Late EPC with a cobblestone shape appear late at 2 to 3 weeks, show exponential growth at 4 to 8 weeks, and live up to 12 weeks. Early EPC are different from late EPC in the expression of VE-cadherin, Flt-1, KDR, and CD45. In addition, early EPC promote vessel growth mainly by their paracrine function whereas late EPC display vasculogenic properties.39 Finally, transplanted EPC derived from CD14+ or CD14- cells were shown to incorporate into vascular structures of nude mice after hindlimb ischaemia and significantly improved neovascularization, supporting the observation of a marked overlap between inflammatory cells and EPC.40


   5. Type of inflammatory cells and mechanisms of pro-angiogenic/pro-arteriogenic activities
Top
 Abstract
 1. Introduction
 2. Inflammation and hypoxia...
 3. Inflammation and mechanical...
 4. Inflammation and progenitor...
 5. Type of inflammatory...
6. Conclusions
 Funding
 References
 
Upregulation of chemoattractant molecules triggers infiltration of different types of inflammatory cells in the ischaemic area. The levels of monocytes directly correlate with the intensity of neovascularization. Monocyte concentrations in peripheral blood were manipulated by single injection of the antimetabolite 5-fluorouracil (5-FU), resulting in a marked rebound effect after a phase of depletion. Seven days after femoral artery ligation, collateral conductance and the number of visible collateral arteries increased in the rebound group. This increase is associated with an increase in monocyte accumulation within the thigh 3 days after surgery. In a second animal model (129S2/SvHsd mice), 5-FU treatment causes a remarkable decrease in blood monocyte numbers at day 4, followed by a rebound effect at day 12. Foot blood flow, assessed by laser-Doppler imaging before and at various time points after surgery, increased from day 7 through day 21 in mice from the rebound group. In contrast, ligation during the phase of monocyte depletion results in a reduction of blood flow reconstitution. This inhibition is reversed by injection of isolated monocytes.41 T lymphocytes have also been shown to mediate post-ischaemic neovascularization. Hence, nude mice or CD4+ T lymphocyte-deficient mice exhibit a significant reduction in post-ischaemic vessel growth.42,43 In addition, CD8-deficient mice display reduced IL-16 expression and decreased CD4+ T-cell recruitment at the site of collateral vessel development. Exogenous CD8+ T cells, infused into CD8-deficient mice immediately after femoral artery ligation, selectively home to the ischaemic hindlimb and express IL-16. The restoration of IL-16 expression results in significant CD4+ mononuclear cell infiltration into the ischaemic limb, faster blood flow recovery, and reduced hindlimb muscle atrophy and fibrosis.44

Recently, the role of natural killer (NK) cells has been highlighted. Collateral growth is impaired in C57BL/6 mice depleted for NK cells by anti-NK1.1 antibodies, and in NK cell-deficient transgenic mice. Vessel growth is, however, unaffected in Ja281-knockout mice that lack NK1.1+ NK T cells, indicating that NK cells, rather than NK T cells, are involved in collateral growth.45 The time course of perfusion recovery in the absence of NK or CD4 T cells suggest that NK cells play a role in the initiation of collateral growth.

Conversely, polymorphonuclear leukocytes (PMN) display anti-angiogenic properties. Hence, the addition of PMN to peripheral blood mononuclear cells and platelets attenuated blood perfusion and capillary formation in athymic nude mice with unilateral hindlimb ischaemia.46 Circulating neutrophils adhere to the vascular endothelium, and the activated neutrophils have the potential to mediate endothelial injury by generating high levels of oxygen metabolites or releasing lysosomal proteinases. Reactive oxygen species (ROS) including superoxide, hydrogen peroxide, hydroxyl anion, and reactive nitrogen species, such as nitric oxide and peroxynitrite, are biologically active oxygen derivatives that are increasingly recognized to play major roles in vascular biology through redox signalling.47–49 Each of these species is derived from specific enzymatic or chemical reactions. A predominant source of ROS in the normal vessel is thought to be a family of membrane-associated NADPH oxidases.47,48,50 The NADPH oxidase as found in neutrophils and endothelial cells47,48,51 consists of a membrane-localized cytochrome b558 comprised of two subunits, gp91phox (or Nox 2) and p22phox, as well as cytosolic components p47phox and p67phox. The small GTPase Rac1 is also necessary for full NADPH oxidase activity. ROS have been suggested as important mediators of angiogenesis. H2O2 stimulates cell migration and proliferation in endothelial cells52 and ROS directly modulate VEGF-A expression and vascular smooth muscle cell proliferation.53 Previous reports also suggest that both the gp91phox-containing NADPH oxidase and Rac1 play a major role in VEGF-A-induced endothelial cell proliferation.54 Similarly, mice lacking gp91phox displayed impaired post-ischaemic neovascularization.55 Of interest, ROS was reported to stimulate post-ischaemic revascularization at low concentrations but to inhibit it at high concentrations.56 In ischaemic tissue, radicals were mostly derived from neutrophils, as shown by marked reduction after the administration of neutrophil NADPH oxidase inhibitors and a monoclonal antibody against neutrophil CD18 adhesion molecule. ROS may act through their ability to induce tissue factor expression and activity.57,58 Reduction of radical generation was associated with a significantly smaller infarct size and a significant increase in coronary flow.57

Neutrophils also release lysosomal proteinases such as elastase. Elastase has been shown to mediate endothelial cell detachment in vitro through digestion of endothelial cell surface proteins including fibronectin.59 In the model of hindlimb ischaemia, neutrophil elastase inhibitor completely reversed the inhibitory effect of PMN, suggesting that neutrophil elastases rather than oxygen metabolites are the responsible anti-angiogenic molecules.46

Platelet activation also occurs in acute ischaemic events. A growing body of evidence indicates that platelets play a major role in inflammation, and activated platelets promote leukocyte arrest on the vascular endothelium.60 Platelets also contain both angiogenic (VEGF-A, ANG-1, PDGF, bFGF, thrombin) and anti-angiogenic growth factors (thrombospondin, PF-4, endostatin). However, despite the presence of anti-angiogenic factors, the overall effect of platelets or their thrombin-induced releasate on angiogenesis is stimulatory, suggesting that this is the predominant mode.61 In particular, thrombin has been shown to promote vessel growth. Suppression of thrombin-generated coagulation, using anticoagulant drugs, immediately after tissue ischaemia induction hampers the in vivo neovascularization response in a rodent hindlimb ischaemia model.62 Thrombin as well as its PAR-1 receptor activation peptide increased vascular regulatory proteins and growth factors: matrix metalloproteinase (MMP)-1, MMP-2, VEGF-A, Ang-2, and receptors VEGFR2 and CXCR2 in endothelial cells. Thrombin can also stimulate the release of VEGF-A and ANG-1 from platelets as well as induce tube formation of endothelial cells in a matrigel membrane system.61 Thrombin markedly upregulates growth-regulated oncogene-{alpha} (GRO-{alpha}) in several tumour cell lines as well as endothelial cells. GRO-{alpha} is a CXC chemokine with angiogenic properties following ligation of its CXCR2 receptor. GRO-{alpha} enhances angiogenesis in the chick chorioallantoic membrane assay, suggesting that GRO-{alpha} mediates the pro-angiogenic effect of thrombin.63

Platelets also appear to serve as ‘bridging’ cells that can both chemoattract EPC and directly support their adhesion by providing a sticky surface. Platelets provide the critical signal that recruits bone marrow-derived progenitor cells to sites of vascular injury. Binding of bone marrow cells to platelets involves both P-selectin and GPIIb integrin on platelets. Activated platelets also secrete the chemokine SDF-1{alpha}, thereby supporting further primary adhesion and migration of progenitor cells through CXCR4 signaling.64 In addition, co-incubation of EPC with platelets for 5 days induces differentiation of EPC from mature endothelial cells.65 Human EPC also express functional PAR-1. Thrombin-induced PAR-1 activation promotes cell proliferation and CXCR4-dependent migration and differentiation, leading to a pro-angiogenic effect.66

Taken together, one can propose the following scheme: in the setting of ischaemia, CD8+ T cells infiltrate the site of collateral vessel growth and recruit CD4+ mononuclear cells through the expression of IL-16. CD4+ T cells control collateral growth to acute ischaemia, at least in part, by recruiting monocytes to the site of active collateral artery formation, which in turn triggers the development of vessels through the synthesis of angiogenic/arteriogenic cytokines (Figure 1).


Figure 1
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  		Figure 1 In the setting of ischaemia, CD8+ T cells infiltrate the site of collateral vessel growth and recruit CD4+ mononuclear cells through the expression of IL-16. CD4+ T cells control the arteriogenic response to acute ischaemia, at least in part, by recruiting monocytes to the site of active collateral artery formation, which in turn triggers the development of vessels through the synthesis of angiogenic/arteriogenic cytokines. NK cells may act in synergy with CD4+ T cells to trigger collateral growth (NK, natural killer cells; Mo, monocytes; GF, growth factor; GFR, growth factor receptor; IL, interleukin; FSS, fluid shear stress).

 
Indeed, the presence of these inflammatory cells is associated with local secretion of several angiogenic/arteriogenic factors, including cytokines such as intereukin-1β, growth factors such as VEGF and basic fibroblast growth factor, and MMP.15,67 In this view, infarcted thrombospondin-1(TSP-1)-deficient mice exhibited sustained macrophage density and subsequently an upregulation of the chemokines MCP-1 and macrophage inflammatory protein-1{alpha}, and the cytokines interleukin-1β, interleukin-6, and TGF-β, leading to more extensive postinfarction remodelling than wild-type mice.68

MMPs have been shown to play an important role in neovascularization. Although their involvement in the onset of vessel growth may suggest that MMPs stimulate vessel growth primarily by matrix degradation, the activities of these proteases are complex and may include other effects such as activation of growth factors and cytokines and degradation of inhibitors.69 In particular, growth factors such as bFGF and VEGF can become liberated from the extracellular matrix after degradation of proteoglycans. The proteolytic modification of growth factors can also change their properties. Hence, MMP-3 and MMP-9 cleave VEGF-A165 to a smaller molecule with properties similar to VEGF-A121.70 Finally, protease interaction with integrins at the cell surface of migrating leukocytes may facilitate their migration through fibrinous matrices.69 Neovascularization is increased in ischaemic hindlimb of mice deficient in the anti-inflammatory cytokine IL-10.71 Such an effect is blocked by MMP inhibition, despite a sustained upregulation of VEGF.72 Leukocyte infiltration in the infarcted heart and subsequent infarct revascularization are reduced in plasminogen activator/MMP9-deficient mice confirming the crucial link between inflammation, proteinases and vessel growth.73 Although endothelial cells express a substantial level of MMP-9, macrophage MMP-9 participates in capillary branching. Transplantation of wild-type bone marrow into the MMP-9-deficient mice restores capillary branching, further supporting the contribution of bone marrow-derived macrophages in supplying the necessary MMP-9.74 Inflammatory cells may also secrete specific pro-angiogenic factors. A macrophage-derived peptide, PR39, inhibits the ubiquitin-proteasome-dependent degradation of HIF-1{alpha} protein, resulting in accelerated formation of vascular structures in vitro and increased myocardial vasculature in mice.75 PR39 also binds to the {alpha}7 subunit of the 26S proteasome and blocks degradation of NF-{kappa}B inhibitor I{kappa}B{alpha} by the ubiquitin-proteasome pathway.76

Finally, inflammation may also be involved in the pro-angiogenic/arteriogenic activities of numerous factors. Hence, severe hindlimb ischaemia stimulated MCP-1 expression that was strongly enhanced by FGF-2 gene transfer, and a blockade of MCP-1 activity via a dominant negative mutant as well as a deficiency of its functional receptor CCR2 resulted in the diminished recovery of blood flow attributable to adaptive and therapeutic neovascularization.77 PlGF stimulated inflammation, angiogenesis, and collateral growth in ischaemic heart and limb. The pro-inflammatory effects of PlGF were attributable to increased mobilization of bone marrow-derived myeloid progenitors into the peripheral blood; enhanced infiltration of VEGF receptor type I-expressing leukocytes in inflamed tissues and sustained activation of myeloid cells.78 Hormones such as angiotensin II have also been shown to control neovascularization.79–81 Infiltration of inflammatory MNC, including macrophages and T lymphocytes, is suppressed in the ischaemic tissues of angiotensin II type 1 receptor (AT1)a-deficient mice. The impaired neovascularization in AT1a-deficient mice is rescued by intramuscular transplantation of MNC obtained from wild-type mice, further indicating that the angiotensin II-AT1 receptor pathway promotes vessel growth by supporting inflammatory cell infiltration and angiogenic cytokine expression.80,82


   6. Conclusions
Top
 Abstract
 1. Introduction
 2. Inflammation and hypoxia...
 3. Inflammation and mechanical...
 4. Inflammation and progenitor...
 5. Type of inflammatory...
 6. Conclusions
Funding
 References
 
Inflammatory cells accumulate in hypoxic and non-hypoxic areas where they respond to these microenvironmental cues and contribute to neovascularization. In most cases, the phenotype switch appears to include the induction of a number of pro-angiogenic and pro-arteriogenic factors, but the net effect of these on the surrounding tissue is likely to vary with the context. The state of activation and differentiation of each inflammatory cell type is also crucial since macrophages or dendritic cells differentiated from isolated CD14+ cells are significantly less effective in improving neovascularization than isolated monocytes.40,41 In addition, one should consider that some pro-inflammatory cytokines, such as IL-18 and IL-12, display anti-angiogenic activities.83–85 Finally, during the inflammatory reaction, anti-inflammatory cytokines are also produced, modulating the neovascularization process and orchestrating the tissue response to ischaemia.71,72 For example, in the first hours of reperfusion after myocardial infarction, TNF{alpha} release from mast cells induces IL-10 synthesis in the microvascular endothelium. IL-10 expression inhibits angiogenic activity, until the injured area is debrided and a fibrin-based provisional matrix is formed. After the first 24 h of reperfusion, TGFβ-mediated IL-10 downregulation shifts the balance towards angiogenesis.86 TSP-1 has also been described as an inhibitor of vessel growth, as it blocked the formation of new blood vessels in the cornea in vivo in response to basic FGF and blocked endothelial cell tube formation and cell migration in vitro. Expression and release of TSPs by megakaryocytes and platelets function as a major anti-angiogenic switch. TSPs limit the extent of revascularization through inhibition of MMP-9 and impaired release of SDF-1 in a model of hindlimb ischaemia.87 Similarly, blocking TSP receptor CD47 using monoclonal antibodies and decreasing CD47 expression using an antisense oligonucleotide are effective therapeutic approaches to dramatically increase survival of soft tissue subjected to fixed ischaemia. These treatments facilitate rapid vascular remodelling to restore tissue perfusion and muscle viability.88 Prolonged inflammation is observed in CD47-, TSP-1-, or TSP-2-deficient mice accompanied by a local deficiency of T cell apoptosis. Upon activation, normal T cells increase the expression of the proapoptotic Bcl-2 family member BNIP3 (Bcl-2/adenovirus E1B interacting protein) and undergo CD47-mediated apoptosis. Overall, the CD47/BNIP3 pathway may limit inflammation by controlling the number of activated T cells and subsequently may be involved in the angiostatic effect of TSPs.89

Therapeutic strategies based on the stimulation of vessel growth by specific activation of inflammatory cells might be a promising treatment for patients with ischaemic diseases. However, an obvious potential complication is that pro-inflammatory and pro-angiogenic/arteriogenic agents will disseminate and induce unintended inflammation and vascularization in adjacent and perhaps even in distant sites. In this view, MCP-1 intramuscular treatment of ApoE-deficient mice with hindlimb ischaemia induces negative systemic effects on atherogenesis, leading to increased atherosclerotic plaque formation and changes in the cellular content of plaques.90 Similarly, transplantation of BM-MNC induced potent pro-angiogenic effects at the site of ischaemic injury in ApoE-deficient mice but also enhanced atherosclerotic plaque size at a distant site.91 Alternative strategies need to be identified, focusing on either different doses to minimize the pro-atherogenic effects or the use of molecules that might act in an anti-atherogenic fashion. Of interest in this regard is the identification of some anti-inflammatory and anti-atherosclerotic agents with pro-angiogenic properties. Hence, IL-18 binding protein, the endogenous inhibitor of IL-18, stimulates ischaemia-induced neovascularization in association with an activation of VEGF/Akt signalling, making IL-18BP, and other IL-18 inhibitors, suitable candidates for the treatment of ischaemic diseases.84,92

Conflict of interest: nothing to disclose.


   Funding
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 Abstract
 1. Introduction
 2. Inflammation and hypoxia...
 3. Inflammation and mechanical...
 4. Inflammation and progenitor...
 5. Type of inflammatory...
 6. Conclusions
 Funding
References
 
J.S.S. is supported by grants from ANR ‘young investigator’ (JC05-45445) and ‘ANR-05-028-01, Cardiovascular, Obesity and Diabetes’. INSERM U689 is a partner of the European Vascular Genomics Network (EVGN), a Network of Excellence granted by the European Commission (contract No. LSHM-CT-2003-503254).


   References
Top
 Abstract
 1. Introduction
 2. Inflammation and hypoxia...
 3. Inflammation and mechanical...
 4. Inflammation and progenitor...
 5. Type of inflammatory...
 6. Conclusions
 Funding
 References
 

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