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Themed Issue papers |
1 Experimental Medicine and Gene Therapy, National Institute of Biostructures and Biosystems, Osilo and Porto Conte Technological Park, Osilo (Sassari), Italy Department of Internal Medicine, Sassari University, Italy Chair of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, UK
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Abstract |
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(Received 18 January 2005;
accepted after revision 2 March 2005; first published online 18 March 2005)
Corresponding author P. Maddedu: National Institute of Biostructures and Biosystems, viale Sant'Antonio, 07033 Osilo (Sassari), Italy. Email: madeddu{at}yahoo.com
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Introduction |
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Recently, the use of progenitor cells has been proposed as a novel method to stimulate vascular regeneration. Endothelial progenitor cells (EPCs) can be harvested from bone marrow (BM). In addition, EPCs are present in circulating blood, in quantities sufficient to permit autologous transplantation. By virtue of their unique plasticity, progenitor cells can differentiate into vascular and non-vascular elements, thereby replacing various components damaged by ischaemic insult. Angiogenesis gene therapy and progenitor cell transplantation might be used in combination due to reciprocal advantages of the two strategies (Nabel, 2001; Losordo & Dimmeler 2004).
The objective of the present review is twofold: (1) to illustrate the current knowledge of the cellular and biochemical mechanisms implicated in spontaneous angiogenesis; and (2) to discuss the advantages and limitations of therapeutic angiogenesis and stem-cell transplantation for the cure of limb and myocardial ischaemia.
Different models of vascular growth
Angiogenesis. Post-natal neovascularization was originally considered to be limited to angiogenesis, that is the activation of pre-existing endothelial cells (ECs) which proliferate, migrate and sprout in situ. Angiogenic sprouting is essential for the development of several physiological and pathological conditions, such as endometrial proliferation, post-ischaemic recovery, wound healing and cancer growth (Risau, 1997). The process progresses in stages: (i) vasodilatation and extravasation of plasma proteins that provide the provisional scaffold for migrating ECs; (ii) interruption of EC mutual contact and detachment from the basement membrane with contribution of extracellular matrix metalloproteinases (MMPs); (iii) EC migration and tube formation; (iv) stabilization and remodelling of newly formed vessels into three-dimensional networks; and (v) destabilization and regression of unnecessary microvessels. Under conditions of reduced perfusion, hypoxia-inducible transcription factor (HIF) triggers a coordinated response by inducing expression of endothelial growth factors (GFs) (Semenza, 1999). Angiogenesis is also induced by metabolic stimuli, including acidosis and oxidative stress (Carmeliet, 2003).
GFs that guide EC proliferation and migration are called direct angiogenic factors. In addition, indirect angiogenic GFs modulate the release of direct factors from cells recruited into sites of angiogenesis. Factors exploitable for therapeutic angiogenesis have been classified as belonging to GF families, chemokines, transcription factors and substances with pleiotropic activity (Table 1).
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By interacting with endothelial tyrosine kinase VEGF receptors VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR), VEGF-A regulates the progression phase of angiogenesis and induces ECs to proliferate, migrate and survive (Ferrara & Devis-Smyth, 1997; Ferrara, 2003). VEGF-B exists as two protein isoforms, VEGF-B167 and VEGF-B186, resulting from alternatively spliced mRNA. VEGF-B specifically binds to VEGFR-1. However, it also forms heterodimers with VEGF-A, a property that influences receptor specificity and final biological effects. Recent studies indicate that VEGF-B promotes angiogenesis through the activation of protein kinase B (Akt/PKB) and endothelial nitric oxide synthase (eNOS)-related pathways (Silvestre et al. 2003). VEGF-C, with related receptors VEGFR-2 and VEGFR-3 (flt-4), represents an apparently redundant pathway for postnatal angiogenesis. VEGF-C was shown to stimulate NO release from ECs and to induce neovascularization in a rabbit model of hindlimb ischaemia (Witzenbichler et al. 1998). Evidence also indicates a role for VEGF-C in pathological angiogenesis and lymphoangiogenesis (Enholm et al. 1998; Ferrara & Alitalo, 1999). Placenta-derived growth factor (PlGF), which binds VEGFR-1, enhances angiogenesis mainly under pathological conditions (Chen et al. 2004). Inhibition of PlGF by elevated placental soluble VEGFR-1 inhibits angiogenesis in pre-eclampsia (Ahmad & Ahmed, 2004).
It has been argued that VEGF by itself promotes the formation of leaky, unstable capillaries rather then arteriogenesis (Helisch & Schaper, 2003), thus limiting its clinical usefulness. In contrast, co-administration of VEGF with additional factors such as platelet-derived growth factor (PDGF) may result in well-organized neovascularization useful for therapeutic applications (Richardson et al. 2001).
The FGF family. Members of the fibroblast growth factor (FGF) family (approximately 23) promote the recruitment of mesenchymal cells to the vessel wall, an essential mechanism for muscularization of nascent capillaries (Bussolino et al. 1997; Hanahan, 1997). FGF-1, FGF-2 and FGF-4 are potent angiogenic factors and may act synergistically with VEGF (Richardson et al. 2001). In addition, administration of FGF seemingly activates collateral growth by upregulating platelet-derived growth factor-BB (PDGF-BB) receptor expression (Cao et al. 2003). FGF receptors are expressed on ECs, smooth muscle cells and myoblasts. Binding of ligand to FGF receptors activates the extracellular signal-regulated kinase 1 and 2 (ERK 1/2) (Midgley & Khachigian, 2004). Besides being implicated in reparative angiogenesis and cardioprotection, FGFs reportedly contribute to cancer angiogenesis (Giavazzi et al. 2003).
The angiopoietins family. Angiopoietin (Ang)-1, which acts through the Tie-2 receptor, is essential for normal embryonic development (Carmeliet 2003), while in the adult it decreases vascular permeability and stabilizes networks initiated by VEGF, presumably by stimulating an interaction between ECs and pericytes (Suri et al. 1998; Chae et al. 2000). The effect of Ang-1 is seemingly organ- and context-dependent, as it stimulates angiogenesis in skin, ischaemic limbs and some tumours (Jain & Munn, 2000), while suppressing neovascularization in the heart (Visconti et al. 2002).
Ang-2 is highly expressed at sites of normal and pathological vascular remodelling. It contributes to stabilizing the shape of native vessels, rendering a quiescent capillary responsive to VEGF-A. However, in the absence of the appropriate stimulus for vessel growth, expression of Ang-2 in endothelium is associated with vessel regression (Maisonpierre et al. 1997).
Hepatocyte growth factor and platelet-derived growth factor. Hepatocyte growth factor (HGF) activates its receptor c-met expressed by ECs and haematopoietic stem cells, thereby resulting in stimulation of angiogenesis. HGF also exerts anti-apoptotic effects in the infarcted heart by activation of phosphatidyl-3' kinase (PI3-kinase)/Akt pathway (Wang et al. 2004).
PDGF-BB and its receptor PDGFR-ß are essential for vascular stabilization by recruitment of mesenchymal progenitors. Lack of PDGF leads to fragile neovasculature, typical of pathological angiogenesis (Carmeliet, 2003). In contrast, combination of PDGF-BB and VEGF results in the formation of more mature vessels when compared to either factor alone (Richardson et al. 2001).
Insulin-like growth factor family. Insulin-like growth factor I (IGF-I) and II (IGF-II) are 7- to 8-kDa structural homologues of insulin with multifunctional activities including promotion of cell growth, inhibition of apoptosis and induction of cell differentiation (Ren et al. 1999). The IGFs in the circulation are primarily produced in the liver, but many cell types can synthesize IGFs in a paracrine fashion. IGF expression is stimulated by ischaemia and vascular damage, suggesting that these factors have important repair functions (Khorsandi et al. 1992). Consistently, administration of IGF-I stimulates angiogenesis and myogenesis, and induces nerve regeneration after injury, although the pro-angiogenic activity appears less potent than that of other angiogenic factors (Nicosia et al. 1994). IGF-1 in combination with HGF was shown to mobilize resident cardiac stem cells, resulting in cardiac regeneration (Kofidis et al. 2004).
Neurotrophins. Nerve growth factor (NGF) represents the first isolated and best-characterized member of a growing family of neurotrophins, which includes brain-derived neurotrophic factor (BDNF) and neurotrophin 3–5 (NTRs 3–5) (Chao et al. 1998). NGF is known to regulate the survival and differentiation of neurones. We have demonstrated that this neurotrophin also acts as a stimulator of angiogenesis and arteriogenesis (Emanueli et al. 2002c). Thus, chemical signals derived from nerves may drive vascular growth (Calzàet al. 2001). The other way round, NGF is also produced and released by ECs (Emanueli et al. 2002c). In addition, NGF high-affinity tyrosine kinase receptor (trkA) and low-affinity p75 receptor are present on ECs and vascular smooth muscle cells (VSMCs), thus suggesting the existence of paracrine/autocrine loops of the polypeptide on these cells.
NGF exerts direct mitogenic and pro-survival effects on ECs via trkA phosphorylation and subsequent activation of ERK1/2 and VEGF–PI3K–Akt-B–NO pathways (Emanueli et al. 2002c; Cantarella et al. 2002). The functions of p75 remain instead undefined, although recent studies from our group support a role for this receptor acting as a trigger of death signalling in diabetic vasculature (Salis et al. 2004; Graiani et al. 2004). Accordingly, the relative expression of NGF subtype receptors on the cellular surface can provide a bifunctional switch for survival or death decisions.
Chemokines. Cytokines are involved in vascular growth and stabilization, by attracting and prolonging the life-span of monocytes (Carmeliet, 2003). This class of angiogenic cytokines comprises monocyte chemo-attractant protein (MCP-1), granulocyte–macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor-
(TNF-). In contrast, anti-inflammatory cytokines such as interleukin (IL)-10 inhibit angiogenesis.
Transcription factors. As mentioned above, transcription factor HIF modulates angiogenesis by activation of the hypoxia-sensitive transduction element of various GF genes (Semenza, 1999).
Early growth response-1 (Egr-1, also called NGFI-A, Zif268 or Krox24) is a member of a family of zinc finger trans-activators which also includes Egr2/Krox20, Egr3 and Egr4/NGFI-C (Gashler & Sukhatme, 1995), that was originally identified as an immediate-early gene dramatically induced by NGF in PC12 cells (Milbrandt, 1987). Recent studies have documented that Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumour growth (Fahmy et al. 2003).
The homeobox gene Prox1 is expressed in a subpopulation of ECs that, after budding from veins, gives rise to the mammalian lymphatic system. Prox1 expression is significantly increased in cancer lymphangiogenesis (Van der Auwera et al. 2004).
Pleiotropic agents. Trypsin-like enzymes are reportedly involved in angiogenesis. Tissue kallikrein (TK) is a serine proteinase expressed in pancreas, salivary glands and the cardiovascular system. The preferred substrate for TK is low molecular kininogen (KNG), from which the enzyme cleaves vasodilator kinin peptides. Knockouts for kallikrein and kinin receptors are viable, thus suggesting that the kallikrein–kinin system (KKS) is not essential for embryo vasculogenesis. However, recent discoveries by our group indicate a role for the KKS in reparative neovascularization (Emanueli, 2000; Emanueli et al. 2001). In adulthood, kinin B1 receptor and tissue kallikrein gene expression is upregulated under conditions of myocardial or limb ischaemia (Tschope et al. 2000; Emanueli et al. 2002a). The functional importance of these expressional changes is documented by the fact that the native angiogenic response to ischaemia is blunted by chronic B1 receptor antagonism or genetic deletion of the same receptor (Emanueli et al. 2002a). Furthermore, disruption of kinin B2 receptor gene results in myocardial capillary rarefaction and ischaemia with ageing (Maestri et al. 2003).
Activation of kinin receptors is followed by Ser473-phosphorylation of Akt, with the subsequent release of NO and stimulation of prostaglandin (PG) synthesis (Emanueli et al. 2004a). Kinins may also modulate the expression of FGF-2 (Parenti et al. 2001). Cellular mechanisms activated by human TK include kinin-induced leucocyte chemotaxis, which may result in amplification of the angiogenic process (Emanueli & Madeddu, 2001b). It is noteworthy that VEGF-A does not play a major role in TK-induced angiogenesis as indicated by the lack of inhibitory effect by VEGF-A neutralizing antibody, VEGF-receptor 2 (VEGF-R2) antagonist or adenoviral vector-carrying soluble VEGF-receptor 1 (VEGF-R1) gene (Emanueli et al. 2004a).
Proteinase-activated receptors (PARs) are expressed by the cardiovascular system and mediate vasodilatation, plasma protein extravasation and EC proliferation, all regarded as essential steps for neovascularization. We recently investigated the angiogenic action of PAR-2 signalling in vivo (Milia et al. 2002). The effect of the PAR-2-activating peptide (PAR-2AP, or SLIGRL-NH2) was assessed in the absence of ischaemia, and the therapeutic potential of PAR-2AP and the PAR-2 agonist trypsin were also tested in mice subjected to unilateral limb ischaemia. PAR-2AP increased capillarity in normoperfused adductor skeletal muscles, whereas neither the vehicle of the PAR-2AP nor the PAR-2 reverse peptide (PAR-2RP, or LRGILS-NH2) produced any effect. In addition, both PAR-2AP and trypsin enhanced reparative angiogenic response to limb ischaemia, an effect that was not produced by PAR-2RP or the vehicle of PAR-2 agonists. Potentiation of reparative angiogenesis by PAR-2AP or trypsin resulted in an accelerated haemodynamic recovery and enhanced limb salvage.
Evidence supports a role of coagulation factors as angiogenic triggers. For instance, thrombin interacts with alpha(v)beta(3) integrin in ECs at the molecular and cellular level. Integrins are cell-surface receptors that transmit bidirectional information inside and outside the EC. Interaction of thrombin with integrins on vascular cells seems to activate the angiogenesis switch (Tsopanoglou et al. 2004).
Frizzled A. Proteins of the wingless (Wnt) family are regarded as regulators of cardiomyogenesis and vasculogenesis. Wnt genes relate to Drosophila wingless and encode for secreted glycoproteins. Wnt bind to Frizzled (FRZ) receptors thereby activating the so-called ‘canonical pathway’ which leads to stabilization of ß-catenin through inactivation of glycogen kinase 3-ß (GSK-3ß), activation of transcription factors and induction of Wnt-responsive genes. A non-canonical pathway involving protein kinase C (PKC) seems to be involved in differentiation of human circulating progenitor cells to cardiomyogenic cells (Koyanagi et al. 2005). FRZ-A is expressed not only by cardiomyocytes and EPCs but also by mature ECs. This protein plays key roles in vascular cell proliferation and is able to control in vivo angiogenic response (Dufourcq et al. 2002).
The Akt–NO pathway. The PI3K–Akt pathway increases NO production by direct phosphorylation of eNOS. NO is highly regulated by various stimuli and growth factors, such as FGF and VEGF. The other way round, it is regarded as a downstream mediator of VEGF and other angiogenic factors. Previous work has established the involvement of PI3K–Akt–NO signalling in VEGF, basic FGF (bFGF), transforming growth factor (TGF)-ß ephrin-B4- and sphingosine-1-phosphate-induced angiogenesis (Papapetropoulos et al. 1997a,b; Babaei et al. 1998; Rikitake et al. 2002).
Vasculogenesis. Asahara and Isner's group was the first to document that ‘vasculogenesis’, which is de novo vessel formation by BM-derived EPCs, plays an important role in postnatal neovascularization triggered by ischaemia, wounding or cancer (Takahashi et al. 1999).
EPCs have been identified not only in BM but also in peripheral blood (Asahara 1997, 1999). These cells are rapidly mobilized from BM into the circulation from where they colonize ischaemic areas and differentiate into mature ECs. Similarly, EPCs are mobilized in areas of vascular trauma or acute myocardial infarction (Gill et al. 2001; Shintani et al. 2001). Many angiogenic factors, able to stimulate the growth of mature ECs, are also implicated in EPC recruitment and differentiation. Accordingly, the increase in circulating EPCs was positively correlated with increased plasma VEGF levels in ischaemic patients (Rafii et al. 2002). Recent evidence indicates that, apart from BM, adult stem cells are constitutively present in isolated niches in each organ from where they can form a reservoir for regeneration of adult cells (Beltrami et al. 2003).
Modulators of vasculogenesis. The molecular events regulating vasculogenesis are largely unknown. Mobilization and recruitment of such elements by VEGF is supported by several findings. VEGFR-1 and VEGFR-2 are expressed on EPCs (Rafii et al. 2002). Furthermore, EPCs isolated from the circulation are capable of secreting VEGF in liquid culture (Pelosi et al. 2002). After VEGF administration in mice, EPCs increase in the circulation and display enhanced proliferative and migratory activity (Asahara et al. 1999). Likewise, patients given VEGF gene transfer for the treatment of peripheral ischaemia show a significant increase in circulating EPCs, thus suggesting that VEGF over-expression can mobilize EPCs (Kalka et al. 2000a). In addition to the direct effects on EPC mobilization, VEGF can also induce the release of haematopoietic GFs, such as GM-CSF, by BM endothelial cells (Bautz et al. 2000). Modulation of EPC kinetics has been similarly observed in response to stem cell factor (SCF, or sKitL) (Takahashi et al. 1999). Matrix metalloproteinase (MMP)-9 appears to play an essential role for EPC recruitment from the BM, an effect that involves SCF release (Heissig et al. 2002). The same factors responsible for mobilization may also be implicated in EPC migration and incorporation. For instance, increased statement of VEGF or exogenous VEGF delivery is paralleled by EPC recruitment into sites of vascular injury (Rafii et al. 2002). Accordingly, EPC homing is guided by VEGF and stromal cell-derived factor (SDF)-1 (Yamaguchi et al. 2003). The latter binds to the chemokine receptor CXCR-4, which is highly expressed on EPCs (Mohle et al. 1998).
Arteriogenesis. Arteries provide the bulk flow to tissue, thus interconnection of the arterial system is necessary to give relief to ischaemic organs. The mechanisms of angiogenesis and arteriogenesis differ significantly. Arteriogenesis is driven by shear stress rather than by hypoxia. Altered shear stress stimulates ECs to send chemo-attractant signals to monocytes (Heil & Schaper, 2004). These cells produce GFs and proteinases, which promote VSMC proliferation. The identification of substances regulating collateralization has great relevance from a therapeutic viewpoint. Members of FGF family and PDGF-BB are involved in arteriogenesis, while VEGF seems to stimulate capillary growth more efficiently (Carmeliet, 2003). In addition, we have recently shown that TK is a potent arteriogenic factor, giving origin to arterioles that can persist over 2 months after a single injection of TK gene into mouse adductor muscle (Emanueli et al. 2004a).
Vascular regression. Vessel destabilization is a natural process that intervenes to finish the angiogenic process once perfusion matches metabolic demand. In general, there is a perfect balance between the optimal number of capillaries and cells. In skeletal muscle this ratio is equal to 1, providing the optimal distance for oxygen and nutrient diffusion from capillary to cells. When too many vessels are generated, compensatory mechanisms intervene to switch off the angiogenic programme. There are, however, different ways by which the angiogenic process is terminated. In healthy animals, neo-angiogenesis generally results in a well-organized and persistent vascular network. In contrast, under conditions such as diabetes, proliferating ECs are committed to premature death by apoptosis. This generates a vicious cycle that leads to hypoxia, inefficient stimulation of EC growth jeopardized by activation of apoptosis, capillary rarefaction and eventually organ failure (Emanueli et al. 2002b, 2004b).
Various factors contribute to vessel destabilization. Thrombospondins inhibit angiogenesis through direct effects on ECs and indirect effects on GF mobilization or activation (Dimmeler & Zeiher, 2000). Ang-2 acts as destabilizator at low levels of VEGF expression (Carmeliet, 2003). Inhibitory Per–Arnt–Sim (PAS) domain protein, C-reactive protein, chemokines binding CXCR3, VEGF soluble receptors Flt1 and Tie2, and proteinase products (such as fragments of kininogen and angiotensinogen) inhibit angiogenesis and contribute to vessel regression (Emanueli & Madeddu, 2001a).
Disease-related impairment of angiogenesis and vasculogenesis
Under disease conditions, impaired neovascularization results in part from diminished vascular GF production. However, endogenous expression of cytokines is not the only factor responsible for the deficit. In fact, primary dysfunction of ECs may configure a picture that we have defined as endotheliopathy (Emanueli & Madeddu, 2001a). For instance, diabetic or hypercholesterolaemic animals – like patients affected by similar diseases – exhibit alterations in EC proliferation and viability (Van Belle et al. 1997; Rivard et al. 1999a). Excessive apoptotic endothelial and muscular cell loss progressively occurs in hindlimbs of diabetic animals and rapid acceleration occurs during arterial obstruction (Emanueli et al. 2004b).
Ageing, another condition associated with impaired neovascularization, might also lead to dysfunctional EPCs and defective vasculogenesis (Rivard et al. 1999b). Indeed, results from Asahara's group indicate that transplantation of EPCs from old into young mice produces minimal neovascularization as compared to transplantation of EPCs from young animals (Murayama et al. 2001). Consistently, EPCs from older patients with clinical ischaemia have significantly less therapeutic effect in rescuing ischaemic hindlimb of mice compared with those from younger ischaemic patients (Masuda & Asahara, 2003). These studies provide evidence to support an age- and/or disease-dependent impairment in angiogenesis/vasculogenesis.
Diabetes also compromises EPC regenerative potential. Recently, Vasa et al. (2001) have evaluated EPC kinetics and their relationship to clinical disorders. They showed that the number and migratory activity of circulating EPCs inversely correlates with risk factors for coronary artery disease, such as smoking, family history and hypertension. Hill et al. (2003) reached the conclusion that circulating EPCs may represent a surrogate biological marker for assessing cardiovascular risk.
Therapeutic angiogenesis
Rationale. Owing to the shortage of endogenous GFs in aged, atherosclerotic patients, it would be therapeutically useful to provide ischaemic heart and limb muscles with exogenous supplements. Similarly, EPC auto-transplantation has been proposed as a way to promote vasculagenesis in patients with myocardial and limb ischaemia.
Dosage. At variance with traditional drugs, the effective dosage of angiogenesis gene therapy is hard to predict because it depends on the infectivity of the viral vector and half-life of the transduced angiogenic molecule. Transgenes carrying a secretory signal sequence have more chances to reach adjacent tissue. Nevertheless, even angiogenic GFs lacking a signal sequence might be released as a result of lysis of infected cells or by a non-classical pathway.
The localization of transgene product can be monitored by different techniques, including immunohistochemistry. However, few studies have addressed the relation between infecting dosage and biological effects. We found that low-dosage gene therapy can be successfully applied to stimulate angiogenesis. In addition, incremental rises of recombinant angiogenic protein do not necessarily produce additional effects, possibly due to saturation of downstream mechanisms or activation of contra-regulatory factors (Emanueli et al. 2004a).
Biological effects of angiogenesis gene therapy are highly dependent on the modality and volume of gene injection (Yla-Herttuala et al. 2004). Inverse transfection efficiency relative to body weight was evidenced by cumulative observations in different species. Mice displayed 60-fold, and rats 50-fold, increased capacity of being infected as compared with pigs or humans. This is because of greater tissue diffusion of gene transfer vectors and smaller volume of rodent skeletal and myocardial muscle. Tissue damage occurs more easily during manipulation of small animals, which may further facilitate transduction efficiency. An additional concern is that preclinical studies are generally performed in otherwise healthy animals, which hardly reflect pathological conditions.
Gene targeting to specific vascular sites. Once, the endothelium was considered a homogeneously inert population of elements separating the circulation from surrounding tissue. Established evidence indicates instead that functional and structural diversity (including heterogeneous responsiveness to angiogenesis factors) is the result of molecular differences between EC populations (Carmeliet, 2003). Recently, organ-specific endothelial antigens have been characterized using in vivo phage display, a technique in which peptide libraries, expressed on the surface of bacteriophages, bind to EC surface molecules. In vivo phage display creates a map of addresses that can be used for targeting therapeutic agents to tissues affected by vascular disease or cancer (Trepel et al.). In the future, this procedure might hopefully overcome the limitations and potential adverse effects of viral vector-based gene transfer.
Angiogenic agents for the treatment of ischaemic diseases. Therapeutic angiogenesis postulates that supplementation with GFs would overcome the endogenous deficit of cytokines and result in a more robust angiogenic response (Henry & Abraham, 2000). Potentiation of the microcirculation by therapeutic angiogenesis has been applied in models of myocardial and peripheral ischaemia and subsequently exploited for the treatment of wound healing and peripheral neuropathy. Following successful application in animal models (by an overwhelming series of experimental studies not reported in this review), these concepts have been transferred from the bench to the bedside.
A general consensus exists regarding the need of further optimization of therapeutic angiogenesis. We know that a single injection of recombinant proteins results in scarce therapeutic effect. Plasmid vectors have limited infectivity potential, thereby leading to low-level expression of curative genes. So far, the most effective way to delivery an angiogenic substance is by gene transfer through an adenoviral vector. Unfortunately, immunity to adenoviruses differs widely among the population, which may significantly reduce the therapeutic impact of the strategy. Furthermore, activation of immune reaction can preclude efficacy of subsequent administrations.
In the clinic, the approach was initially tested for the cure of patients in whom conventional treatments were ineffective or technically not amenable. Results of first clinical trials, mainly using VEGF or FGF gene transfer, demonstrate that therapeutic angiogenesis is safe, attenuates clinical symptoms (e.g. claudication and angina) and improves indices of cardiac function (Table 2). Resolution of perfusion rest defects after angiogenesis gene transfer is consistent with the possibility that foci of hibernating myocardium have been resuscitated as the result of therapeutic neovascularization. Nevertheless, the search for the optimal angiogenic substance can not yet be considered concluded.
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The aim of the FGF Initiating RevaScularization Trial (FIRST) (Simons et al. 2002) was to evaluate the efficacy and safety of recombinant FGF2 in patients with coronary artery disease. FIRST was a multicentre, randomized, double-blind, placebo-controlled trial of a single intracoronary infusion of FGF2 at 0, 0.3, 3 or 30 µg kg–1 (n= 337 patients). Exercise tolerance was increased at 90 days in all groups and was not significantly different between placebo and FGF-treated groups. FGF2 reduced angina symptoms as measured by the angina frequency scores. These differences were more pronounced in highly symptomatic patients. None of the differences were significant at 180 days because of continued improvement in the placebo group. Adverse events were similar across all groups, except for hypotension, which occurred with higher frequency in the group receiving 30 µg kg–1 FGF2.
The therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (TRAFFIC) study (Lederman et al. 2002) was a randomised trial investigating whether one or two doses of intra-arterial recombinant FGF-2 improves exercise capacity in patients with moderate-to-severe intermittent claudication. Patients were randomly assigned to bilateral intra-arterial infusions of placebo on days 1 and 30 (n= 63); FGF-2 (30 µg kg–1) on day 1 and placebo on day 30 (single dose, n= 66); or FGF-2 (30 µg kg–1) on days 1 and 30 (double dose, n= 61). Results indicate a significant increase in peak walking time at 90 days; repeat infusion at 30 days was no better than one infusion.
The objectives of the Angiogenic GENe Therapy (AGENT) (Grines et al. 2002) trial were to evaluate the safety and anti-ischaemic effects of five ascending doses of Ad5-FGF4 in patients with angina and to select potentially safe and effective doses for subsequent study. Seventy-nine patients with chronic stable angina (Canadian Cardiovascular Society class 2 or 3) were randomly assigned in a double-blind procedure (1: 3) to placebo (n= 19) or adenovirus type 5 FGF4 (Ad5-FGF4) (n= 60). Single intracoronary administration of Ad5-FGF4 was safe and well tolerated with no immediate adverse events. Fever of < 1-day duration occurred in three patients in the highest-dose group. Transient, asymptomatic elevations in liver enzymes occurred in two patients in the lower-dose groups. Serious adverse events during follow-up (mean, 311 days) were not different between placebo and Ad5-FGF4. Overall, patients who received Ad5-FGF4 tended to have greater improvements in exercise time at 4 weeks. A protocol-specified, subgroup analysis showed the greatest improvement in patients with more severe symptoms.
The objectives of Kuopio's andiogenesis trial (KAT) (Makinen et al. 2002) were to evaluate safety and angiographic and haemodynamic responses of local catheter-mediated VEGF gene therapy in ischaemic lower-limb arteries after percutaneous transluminal angioplasty. Eighteen patients received 2 x 1010 plaque-forming units (pfu) VEGF-adenovirus (VEGF-Ad), 17 patients received VEGF-plasmid/liposome (VEGF-P/L; 2000 µg of VEGF plasmid), and 19 control patients received Ringer's lactate buffer at the angioplasty site. Anti-adenovirus antibodies increased in 61% of the patients treated with VEGF-Ad. For the primary endpoint, follow-up angiography revealed increased vascularity in the VEGF-treated groups distally to the gene transfer site and in the VEGF-Ad group in the region of the clinically most severe ischaemia.
Therapeutic vasculogenesis. Transplantation of exogenous EPCs, isolated from adult peripheral blood, cord blood or BM, has shown great promise as a potential means to treat cardiovascular disease (Murohara et al. 2000; Kalka et al. 2000b; Orlic et al. 2001; Kawamoto et al. 2001; Madeddu et al. 2004). In animal models of ischaemia, transplanted EPCs augmented reparative neovascularization either through differentiation into mature ECs or indirectly through paracrine stimulation of resident EC proliferation. Furthermore, EPCs interfere with ischaemia-induced cardiomyocyte apoptosis, thus preventing inappropriate cardiac remodelling and failure (Kocher et al. 2001).
Preliminary evidence suggests that the strategy may have therapeutic use for the treatment of ischaemic disease in man. The Therapeutic Angiogenesis by Cell Transplantation (TACT) (Tateishi-Yuyama et al. 2002) study consisted of a randomized controlled trial in patients with peripheral artery disease. Intramuscular injection of BM-derived mononuclear cells produced a significant increase in transcutaneous oxygen pressure, rest pain and pain-free walking time, whereas freshly isolated peripheral blood monocytes did not exert any effect.
In another recent study, Strauer et al. (2002) infused BM-derived mononuclear cells via an intracoronary balloon catheter (intended to generate an ischaemic gradient favourable for EPC homing), 5–9 days after the acute myocardial infarction. In comparison to 10 non-randomized control patients, who did not undergo cell therapy or additional catheterization, BM-derived mononuclear cell infusion enhanced regional infarct region perfusion as assessed by thallium scintigraphy. Moreover, stroke volume, end-systolic volume and contractility indices were improved after cell therapy.
In the Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial (Assmus et al. 2002), recruited patients were randomly allocated to receive either BM-derived mononuclear cells (immediately infused after preparation) or EPCs (ex vivo expanded for 3 days). Cell therapy was performed 4 days after myocardial infarction. Both approaches improved the global ejection fraction, as assessed by left ventricular angiography, compared with a non-randomized control patient collective. In a subgroup of the total series, magnetic resonance imaging (MRI) studies confirmed the functional improvement by EPCs.
Additional trials, including the first randomized study on patients with acute myocardial infarction receiving intracoronary infusion of BM-derived mononuclear cells or no treatment, showed haemodynamic improvements in patients receiving cell therapy (Wollert et al. 2003; Stamm et al. 2003; Perin et al. 2003; Tse et al. 2003; Fuchs et al. 2003).
However, many issues must be settled before the EPC transplantation can be extensively and safely applied to patients, including establishing the source, optimal dosage and cell subfraction most suitable for therapeutic purpose. Technical improvements are also necessary to overcome the problems arising from the substantial loss of functional EPCs in the first few hours after transplantation. The therapeutic implications of this phenomenon have been probably underestimated and the relevance of apoptosis in jeopardizing vasculogenesis still awaits experimental and clinical documentation. Possible ways to improve efficacy encompass: (1) local instead of systemic delivery; (2) chemokine supplementation to promote BM-derived EPC mobilization; (3) enrichment procedures or culture-expansion of EPCs; and (4) enhancement of EPC function by gene transduction, that is gene modified EPC therapy.
Transplantation of genetically manipulated EPCs. Advances in our ability to genetically manipulate cells ex vivo have provided the technological platform to implement EPC biology and circumvent the potential hazard of direct gene transfer. Furthermore, the approach eliminates the drawback of immune response against viral vectors and makes feasible repeating the therapeutic procedure in the case of injury recurrence. Another advantage is represented by the possibility of using EPCs as a delivery system for curative substances to target organs. Thus, genetic manipulation of stem cells represents a novel option for tissue regeneration.
Conclusions and perspectives
Once considered an alternative for no-option patients, therapeutic angiogenesis is rapidly expanding its possible applications. Recent progress in the understanding of the molecular and cellular mechanisms of angiogenesis/vasculogenesis is expected to speed up the clinical development of biological revascularization. In this respect, great hope resides in the use of human embryonic stem cells as a potent tool for tissue regeneration. It is envisioned that these new approaches of regenerative medicine will open unprecedented opportunities for the care of life-threatening diseases.
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References |
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TopAbstractIntroductionReferences |
|---|
Asahara T (1997). Isolation of putative progenitor endothelial cells for angiogenesis. Science 275, 965–967.
Asahara
T (1999). Bone marrow origin of endothelial progenitor cells responsible for post-natal vasculogenesis in physiological and pathological neovascularization. Circ Res
85, 221–228.
Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H et al. (1999). VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 18, 3964–3972. 10.1093/emboj/18.14.3964[CrossRef]
Assmus
B, Schachinger
V, Teupe
C, Britten
M, Lehmann
R, Dobert
N
et al. (2002). Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation
106, 3009–3017.
Babaei
S, Teichert-Kuliszewska
K, Monge
JC, Mohamed
F, Bendeck
MP
&
Stewart
DJ (1998). Role of nitric oxide in the angiogenic response in vitro to basic fibroblast growth factor. Circ Res
82, 1007–1015.
Bautz F, Rafii S, Kanz L & Mohle R (2000). Expression and secretion of vascular endothelial growth factor-A by cytokine-stimulated hematopoietic progenitor cells: possible role in the hematopoietic microenvironment. Exp Hematol 28, 700–706.[CrossRef][Medline]
Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S et al. (2003). Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114, 763–776.[CrossRef][Medline]
Bussolino F, Mantovani A & Persico G (1997). Molecular mechanisms of blood vessel formation. Trends Biochem Sci 22, 251–256.[CrossRef][Medline]
Calza
L, Giardino
L, Giuliani
A, Aloe
L
&
Levi-Montalcini
R (2001). Nerve growth factor control of neuronal expression of angiogenetic and vasoactive factors. Proc Natl Acad Sci U S A
98, 4160–4165.
Cantarella
G, Lempereur
L, Presta
M, Ribatti
D, Lombardo
G, Lazarovici
P
et al. (2002). Nerve growth factor–endothelial cell interaction leads to angiogenesis in vitro and in vivo. FASEB J
16, 1307–1309.
Cao R, Brakenhielm E, Pawliuk R, Wariaro D, Post MJ, Wahlberg E et al. (2003). Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2. Nat Med 9, 604–613.[CrossRef][Medline]
Carmeliet P (2003). Angiogenesis in health and disease. Nat Med 9, 653–660.[CrossRef][Medline]
Chae
JK, Kim
I, Lim
ST, Chung
MJ, Kim
WH, Kim
HG
et al. (2000). Coadministration of angiopoietin-1 and vascular endothelial growth factor enhances collateral vascularization. Arterioscler Thromb Vasc Biol
20, 2573–2578.
Chao M, Casaccia-Bonnefil P, Carter B, Chittka A, Kong H & Yoon SO (1998). Neurotrophin receptors: mediators of life and death. Brain Res Rev 26, 295–301.[CrossRef][Medline]
Chen CN, Hsieh FJ, Cheng YM, Cheng WF, Su YN, Chang KJ & Lee PH (2004). The significance of placenta growth factor in angiogenesis and clinical outcome of human gastric cancer. Cancer Lett 213, 73–82.[CrossRef][Medline]
Dimmeler
S
&
Zeiher
AM (2000). Endothelial cell apoptosis in angiogenesis and vessel regression. Circ Res
87, 434–439.
Dufourcq
P, Couffinhal
T, Ezan
J, Barandon
L, Moreau
C, Daret
D
et al. (2002). FrzA, a secreted frizzled related protein, induced angiogenesis. Circulation
106, 3097–3103.
Emanueli
C (2000). Adenovirus-mediated human tissue kallikrein gene delivery induces angiogenesis in normoperfused skeletal muscle. Arterioscler Thromb Vasc Biol
20, 2379–2385.
Emanueli
C, Minasi
A, Zacheo
A, Chao
J, Chao
L, Salis
MB
et al. (2001). Local delivery of human tissue kallikrein gene accelerates spontaneous angiogenesis in mouse model of hindlimb ischemia. Circulation
103, 125–132.
Emanueli
C, Bonaria Salis
M, Stacca
T, Pintus
G, Kirchmair
R, Isner
JM
et al. (2002a). Targeting kinin B1 receptor for therapeutic neovascularization. Circulation
105, 360–366.
Emanueli
C, Salis
MB, Pinna
A, Stacca
T, Milia
AF, Spano
A
et al. (2002b). Prevention of diabetes-induced microangiopathy by human tissue kallikrein gene transfer. Circulation
106, 993–999.
Emanueli
C, Salis
MB, Pinna
A, Graiani
G, Manni
L
&
Madeddu
P (2002c). Nerve growth factor promotes angiogenesis and arteriogenesis in ischemic hindlimbs. Circulation
106, 2257–2262.
Emanueli
C, Salis
MB, Van Linthout
S, Meloni
M, Desortes
E, Silvestre
JS
et al. (2004a). Akt/protein kinase B and endothelial nitric oxide synthase mediate muscular neovascularization induced by tissue kallikrein gene transfer. Circulation
110, 1638–1644.
Emanueli
C, Graiani
G, Salis
MB, Gadau
S, Desortes
E
&
Madeddu
P (2004b). Prophylactic gene therapy with human tissue kallikrein ameliorates limb ischemia recovery in type 1 diabetic mice. Diabetes
53, 1096–1103.
Emanueli C & Madeddu P (2001a). Angiogenesis gene therapy to rescue ischemic tissues: achievements and future directions. Br J Pharmacol 133, 951–958. 10.1038/sj.bjp.0704155[CrossRef][Medline]
Emanueli C & Madeddu P (2001b). Targeting kinin receptors for the treatment of tissue ischaemia. Trends Pharmacol Sci 22, 478–484. 10.1016/S0165-6147(00)01761-2[CrossRef][Medline]
Enholm B, Jussila L, Karkkainen M & Alitalo K (1998). Vascular endothelial growth factor-C: a growth factor for lymphatic and blood vascular endothelial cells. Trends Cardiovasc Med 8, 292–297. 10.1016/S1050-1738(98)00026-7[CrossRef][Medline]
Fahmy RG, Dass CR, Sun LQ, Chesterman CN & Khachigian LM (2003). Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth. Nat Med 9, 1026–1032. 10.1038/nm905[CrossRef][Medline]
Ferrara N (2003). The biology of VEGF and its receptors. Nat Med 9, 669–676. 10.1038/nm0603-669[CrossRef][Medline]
Ferrara N & Alitalo K (1999). Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 5, 1359–1364. 10.1038/70928
Ferrara N & Devis-Smyth T (1997). The biology of vascular endothelial growth factor. Endocr Rev 18, 4–25. 10.1210/er.18.1.4
Fuchs
S, Satler
LF, Kornowski
R, Okubagzi
P, Weisz
G, Baffour
R
et al. (2003). Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study. J Am Coll Cardiol
41, 1721–1724. 10.1016/S0735-1097(03)00328-0
Gashler A & Sukhatme VP (1995). Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. Prog Nucleic Acid Res Mol Biol 50, 191–224.[Medline]
Giavazzi
R, Sennino
B, Coltrini
D, Garofalo
A, Dossi
R, Ronca
R
et al. (2003). Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Am J Pathol
162, 1913–1926.
Gill
M, Dias
S, Hattori
K, Rivera
ML, Hicklin
D, Witte
L
et al. (2001). Vascular trauma induces rapid but transient mobilization of VEGFR2+AC133+ endothelial precursor cells. Circ Res
88, 167–174.
Graiani G, Emanueli C, Desortes E, Van Linthout S, Pinna A, Figueroa CD et al. (2004). Nerve growth factor promotes reparative angiogenesis and inhibits endothelial apoptosis in cutaneous wounds of Type 1 diabetic mice. Diabetologia 47, 1047–1054.[Medline]
Grines
CL, Watkins
MW, Helmer
G, Penny
W, Brinker
J, Marmur
JD
et al. (2002). Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation
105, 1291–1297.
Hanahan
D (1997). Signaling vascular morphogenesis and maintenance. Science
277, 48–50. 10.1126/science.277.5322.48
Heil
M
&
Schaper
W (2004). Influence of mechanical, cellular, and molecular factors on collateral artery growth (arteriogenesis). Circ Res
95, 449–458. 10.1161/01.RES.0000141145.78900.44
Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR et al. (2002). Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625–637.[CrossRef][Medline]
Helisch A & Schaper W (2003). Arteriogenesis: the development and growth of collateral arteries. Microcirculation 10, 83–97. 10.1038/sj.mn.7800173[CrossRef][Medline]
Henry
TD, Annex
BH, McKendall
GR, Azrin
MA, Lopez
JJ, Giordano
FJ
et al. (2003). The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation
107, 1359–1365.
Henry TD & Abraham JA (2000). Review of preclinical and clinical results with vascular endothelial growth factors for therapeutic angiogenesis. Curr Interv Cardiol Rep 2, 228–241.[Medline]
Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA & Finkel T (2003). Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348, 593–600. 10.1056/NEJMoa022287
Jain RK & Munn LL (2000). Leaky vessels? Call Ang1!Nat Med 6, 131–132. 10.1038/72212[CrossRef][Medline]
Kalka
C, Masuda
H, Takahashi
T, Kalka-Moll
WM, Silver
M, Kearney
M
et al. (2000a). VEGF gene transfer mobilizes endothelial progenitor cells in patients with inoperable coronary disease. Ann Thorac Surg
70, 829–834. 10.1016/S0003-4975(00)01633-7
Kalka
C, Tehrani
H, Laudenberg
B, Vale
PR, Isner
JM, Asahara
T
et al. (2000b). Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A
97, 3422–3427. 10.1073/pnas.070046397
Kawamoto
A, Gwon
HC, Iwaguro
H, Yamaguchi
JI, Uchida
S, Masuda
H
et al. (2001). Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation
103, 634–637.
Khorsandi MJ, Fagin JA, Giannella-Neto D, Forrester JS & Cercek B (1992). Regulation of insulin-like growth factor-I and its receptor in rat aorta after balloon denudation. Evidence for local bioactivity. J Clin Invest 90, 1926–1931.
Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J et al. (2001). Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7, 430–436. 10.1038/86498
Kofidis
T, de Bruin
JL, Yamane
T, Balsam
LB, Lebl
DR, Swijnenburg
RJ
et al. (2004). Insulin-like growth factor promotes engraftment, differentiation, and functional improvement after transfer of embryonic stem cells for myocardial restoration. Stem Cells
22, 1239–1245. 10.1634/stemcells.2004-0127
Koyanagi M, Haendeler J, Badorff C, Brandes RP, Hoffmann J, Pandur P et al. (2005). Non-canonical wnt signalling enhances differentiation of human circulating progenitor cells to cardiomyogenic cells. J Biol Chem Epub ahead of print.
Lederman RJ, Mendelsohn FO, Anderson RD, Saucedo JF, Tenaglia AN, Hermiller JB et al. (2002). Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet 359, 2053–2058. 10.1016/S0140-6736(02)08937-7[CrossRef][Medline]
Losordo
DW
&
Dimmeler
S (2004). Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part II: Cell-based therapies. Circulation
109, 2487–2491.
Madeddu
P, Emanueli
C, Pelosi
E, Salis
MB, Cerio
AM, Bonanno
G
et al. (2004). Transplantation of low dose CD34+KDR+ cells promotes vascular and muscular regeneration in ischemic limbs. FASEB J
18, 1737–1739.
Maestri
R, Milia
AF, Salis
MB, Graiani
G, Lagrasta
C, Monica
M
et al. (2003). Cardiac hypertrophy and microvascular deficit in kinin B2 receptor knockout mice. Hypertension
41, 1151–1155. 10.1161/01.HYP.0000064180.55222.DF
Maisonpierre
PC, Suri
C, Jones
PF, Bartunkova
S, Wiegand
SJ, Radziejewski
C
et al. (1997). Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science
277, 55–60. 10.1126/science.277.5322.55
Makinen K, Manninen H, Hedman M, Matsi P, Mussalo H, Alhava E et al. (2002). Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study. Mol Ther 6, 127–133. 10.1006/mthe.2002.0638[CrossRef][Medline]
Masuda H & Asahara T (2003). Post-natal endothelial progenitor cells for neovascularization in tissue regeneration. Cardiovasc Res 93, 162–169.
Midgley
VC
&
Khachigian
LM (2004). Fibroblast growth factor-2 induction of platelet-derived growth factor-C chain transcription in vascular smooth muscle cells is ERK-dependent but not JNK-dependent and mediated by Egr-1. J Biol Chem
279, 40289–40295. 10.1074/jbc.M406063200
Milbrandt
J (1987). A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science
238, 797–799.
Milia
AF, Salis
MB, Stacca
T, Pinna
A, Madeddu
P, Trevisani
M
et al. (2002). Protease-activated receptor-2 stimulates angiogenesis and accelerates hemodynamic recovery in a mouse model of hindlimb ischemia. Circ Res
91, 346–352. 10.1161/01.RES.0000031958.92781.9E
Mohle
R, Bautz
F, Rafii
S, Moore
MA, Brugger
W
&
Kanz
L (1998). The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. Blood
91, 4523–4530.
Murayama T (2001). Aging impairs therapeutic contribution of human endothelial progenitor cells to postnatal neovascularization. Circulation 104, II-68.
Murohara T, Ikeda H, Duan J, Shintani S, Sasaki K, Eguchi H et al. (2000). Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest 105, 1527–1536.[Medline]
Nabel E (2001). Stem cells combined with gene transfer for therapeutic vasculogenesis. Magic bullets?Circulation 105, 672–674.
Nicosia RF, Nicosia SV & Smith M (1994). Vascular endothelial growth factor, platelet-derived growth factor, and insulin-like growth factor-1 promote rat aortic angiogenesis in vitro. Am J Pathol 145, 1023–1029.[Abstract]
Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K et al. (2001). Deletion of the hypoxia response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28, 131–138. 10.1038/88842[CrossRef][Medline]
Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B et al. (2001). Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705. 10.1038/35070587
Papapetropoulos A, Desai KM, Rudic RD, Mayer B, Zhang R, Ruiz-Torres MP et al. (1997a). Nitric oxide synthase inhibitors attenuate transforming-growth-factor-ß1 stimulated capillary organization in vitro. Am J Pathol 150, 1835–1844.[Abstract]
Papapetropoulos A, Garcia-Cardena G, Madri JA & Sessa WC (1997b). Nitric oxide production contributes to the angiogenic properties of vascular endothelial growth factor in human endothelial cells. J Clin Invest 100, 3131–3139.[Medline]
Parenti
A, Morbidelli
L, Ledda
F, Granger
HJ
&
Ziche
M (2001). The bradykinin/B1 receptor promotes angiogenesis by up-regulation of endogenous FGF-2 in endothelium via the nitric oxide synthase pathway. FASEB J
15, 1487–1489.
Pelosi
E, Valtieri
M, Coppola
S, Botta
R, Gabbianelli
M, Lulli
V
et al. (2002). Identification of the hemangioblast in postnatal life. Blood
100, 3203–3208.
Perin
EC, Dohmann
HF, Borojevic
R, Silva
SA, Sousa
AL, Mesquita
CT
et al. (2003). Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation
107, 2294–2302.
Rafii S, Heissig B & Hattori K (2002). Efficient mobilization and recruitment of marrow-derived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors. Gene Ther 9, 631–641. 10.1038/sj.gt.3301723[CrossRef][Medline]
Ren J, Samson WK & Sowers JR (1999). Insulin-like growth factor I as a cardiac hormone: physiological and pathophysiological implications in heart disease. J Mol Cell Cardiol 31, 2049–2061. 10.1006/jmcc.1999.1036[CrossRef][Medline]
Richardson TP, Peters MC, Ennett AB & Mooney DJ (2001). Polymeric system for dual growth factor delivery. Nat Biotechnol 19, 1029–1034. 10.1038/nbt1101-1029[CrossRef][Medline]
Rikitake
Y, Hirata
K, Kawashima
S, Ozaki
M, Takahashi
T, Ogawa
W
et al. (2002). Involvement of endothelial nitric oxide in sphingosine-1-phosphate-induced angiogenesis. Arterioscler Thromb Vasc Biol
22, 108–114. 10.1161/hq0102.101843
Risau W (1997). Mechanism of angiogenesis. Nature 386, 671–674. 10.1038/386671a0
Rivard
A, Silver
M, Chen
D, Kearney
M, Magner
M, Annex
B
et al. (1999a). Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol
154, 355–363.
Rivard
A, Fabre
JE, Silver
M, Chen
D, Murohara
T, Kearney
M
et al. (1999b). Age-dependent impairment of angiogenesis. Circulation
99, 111–120.
Salis MB, Graiani G, Desortes E, Caldwell RB, Madeddu P & Emanueli C (2004). Nerve growth factor supplementation reverses the impairment, induced by Type 1 diabetes, of hindlimb post-ischaemic recovery in mice. Diabetologia 47, 1055–1063.[Medline]
Semenza GL (1999). Hypoxia inducible factor 1: master regulator of O2 homeostasis. Curr Opin Genet Dev 8, 588–594. 10.1016/S0959-437X(98)80016-6[CrossRef][Medline]
Shintani
S, Murohara
T, Ikeda
H, Ueno
T, Honma
T, Katoh
A
et al. (2001). Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation
103, 2776–2779.
Silvestre
JS, Tamarat
R, Ebrahimian
TG, Le-Roux
A, Clergue
M, Emmanuel
F
et al. (2003). Vascular endothelial growth factor-B promotes in vivo angiogenesis. Circ Res
93, 114–123. 10.1161/01.RES.0000081594.21764.44
Simons
M, Annex
BH, Laham
RJ, Kleiman
N, Henry
T, Dauerman
H
et al. (2002). Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2. Double-blind, randomized, controlled clinical trial. Circulation
105, 788–793.
Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H et al. (2003). Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 361, 45–46. 10.1016/S0140-6736(03)12110-1[CrossRef][Medline]
Strauer
BE, Brehm
M, Zeus
T, Kostering
M, Hernandez
A, Sorg
RV
et al. (2002). Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation
106, 1913–1918.
Suri C, McClain J, Thurston G, McDonald DM, Zhou H, Oldmixon EH et al. (1998). Increased vascularization in mice overexpressing angiopoietin-1. Science 282, 468–471. 10.1126/science.282.5388.468
Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M et al. (1999). Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 5, 434–438. 10.1038/7434
Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H et al. (2002). Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 360, 427–435. 10.1016/S0140-6736(02)09670-8[CrossRef][Medline]
Trepel M et al. (2002). In vivo phage display and vascular heterogeneity: implications for targeted medicine. Curr Opin Chem Biol 6, 399–404. 10.1016/S1367-5931(02)00336-8[CrossRef][Medline]
Tschope C, Heringer-Walther S, Koch M, Spillmann F, Wendorf M et al. (2000). Upregulation of bradykinin B1-receptor expression after myocardial infarction. Br J Pharmacol 129, 1537–1538. 10.1038/sj.bjp.0703239[CrossRef][Medline]
Tse HF, Kwong YL, Chan JK, Lo G, Ho CL & Lau (2003). Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 361, 47–49. 10.1016/S0140-6736(03)12111-3[CrossRef][Medline]
Tsopanoglou NE, Papaconstantinou ME, Flordellis CS & Maragoudakis ME (2004). On the mode of action of thrombin-induced angiogenesis: thrombin peptide, TP508, mediates effects in endothelial cells via alphavbeta3 integrin. Thromb Haemost 9, 846–857.
Van Belle
E, Rivard
A, Chen
D, Silver
M, Bunting
S, Ferrara
N
et al. (1997). Hypercholesterolemia attenuates angiogenesis but does not preclude augmentation by angiogenic cytokines. Circulation
96, 2667–2674.
Van der Auwera
I, Van Laere
SJ, Van den Eynden
GG, Benoy
I, van Dam
P, Colpaert
CG
et al. (2004). Increased angiogenesis and lymphangiogenesis in inflammatory versus noninflammatory breast cancer by real-time reverse transcriptase-PCR gene expression quantification. Clin Cancer Res
10, 7965–7971.
Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H et al. (2001). Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89, E1–E7.
Visconti
RP, Richardson
CD
&
Sato
TN (2002). Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor (VEGF). Proc Natl Acad Sci U S A
99, 8219–8224. 10.1073/pnas.122109599
Wang Y, Ahmad N, Wani MA & Ashraf M (2004). Hepatocyte growth factor prevents ventricular remodeling and dysfunction in mice via Akt pathway and angiogenesis. J Mol Cell Cardiol 37, 1041–1052. 10.1016/j.yjmcc.2004.09.004[CrossRef][Medline]
