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Am J Physiol Regul Integr Comp Physiol 288: R1432-R1437, 2005; doi:10.1152/ajpregu.00662.2004
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INVITED REVIEW

Adrenomedullin: angiogenesis and gene therapy

Noritoshi Nagaya,1,2 Hidezo Mori,3 Shinsuke Murakami,1 Kenji Kangawa,4 and Soichiro Kitamura5

1Department of Regenerative Medicine and Tissue Engineering, 2Department of Internal Medicine, 3Department of Cardiac Physiology, 4Department of Biochemistry, 5Department of Cardiovascular Surgery, National Cardiovascular Center Research Institute, Osaka, Japan


   ABSTRACT
TOP
 ABSTRACT
ENDOGENOUS AM PRODUCTION IN...
 ANGIOGENIC EFFECTS OF AM...
 THERAPEUTIC ANGIOGENESIS
 GRANTS
 REFERENCES
 
Adrenomedullin (AM) is a potent, long-lasting vasodilator peptide that was originally isolated from human pheochromocytoma. AM signaling is of particular significance in endothelial cell biology since the peptide protects cells from apoptosis, promotes angiogenesis, and affects vascular tone and permeability. The angiogenic effect of AM is mediated by activation of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and focal adhesion kinase in endothelial cells. Both AM and its receptor, calcitonin receptor-like receptor, are upregulated through a hypoxia-inducible factor-1-dependent pathway under hypoxic conditions. Thus AM signaling plays an important role in the regulation of angiogenesis in hypoxic conditions. Recently, we have developed a nonviral vector, gelatin. Positively charged gelatin holds negatively charged plasmid DNA in its lattice structure. DNA-gelatin complexes can delay gene degradation, leading to efficient gene transfer. Administration of AM DNA-gelatin complexes induces potent angiogenic effects in a rabbit model of hindlimb ischemia. Thus gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of tissue ischemia. Endothelial progenitor cells (EPCs) play an important role in endothelial regeneration. Interestingly, EPCs phagocytose ionically linked DNA-gelatin complexes in coculture, which allows nonviral gene transfer into EPCs. AM gene transfer into EPCs inhibits cell apoptosis and induces proliferation and migration, suggesting that AM gene transfer strengthens the therapeutic potential of EPCs. Intravenous administration of AM gene-modified EPCs regenerate pulmonary endothelium, resulting in improvement of pulmonary hypertension. These results suggest that in vivo and in vitro transfer of AM gene using gelatin may be applicable for intractable cardiovascular disease.

regeneration; endothelium; ischemia; pulmonary hypertension

ADRENOMEDULLIN (AM) IS A POTENT, long-lasting vasodilator peptide that was originally isolated from human pheochromocytoma (36). The peptide consists of 52 amino acids with an intramolecular disulfide bond, sharing slight homology with calcitonin gene-related peptide and amylin. Immunoreactive AM is detected in plasma and a variety of tissues including, blood vessels, heart, and lungs (19). Particularly, AM shows a variety of effects on the vasculature that include vasodilatation (23), regulation of permeability (16), inhibition of endothelial apoptosis (31), and promotion of angiogenesis (1, 35, 60). In addition, AM has protective effects against vascular injury, including oxidative stress (33, 69, 84). It is becoming clear that either activation or disruption of AM signaling might contribute to many pathological conditions, including hypertension (22), congestive heart failure (55), pulmonary hypertension (29), neoplastic growth (39), and inflammatory disease (59). To date, the major biological acitivities of AM in vitro and in vivo are 1) vasodilation, 2) diuresis and natriuresis, 3) positive inotropic effect, 4) inhibition of endothelial cell apoptosis, 5) induction of angiogenesis, 6) inhibition of cardiomyocyte apoptosis, 7) suppression of aldosterone production, 8) anti-inflammatory activity, and 9) antioxidant activity. We and others have demonstrated that intravenous administration of AM decreases systemic and pulmonary arterial pressure and induces diuresis and natriuresis (47, 52, 65), suggesting that AM is involved in the regulation of vascular tone and body fluid. Subsequent studies have demonstrated beneficial hemodynamic effects and direct cardioprotective effects of AM infusion in the treatment of congestive heart failure (57, 61–64).

Until recently, only vascular endothelial growth factor (VEGF) (80), fibroblast growth factor (68), platelet-derived growth factor (37), and angiopoietin (74) were known to have profound angiogenic effects. More recently, however, the angiogenic potential of AM has attracted investigators' attention (35, 41, 59, 81). A previous study has shown that vascular abnormalities are present in homozygous AM knockout mice (70), suggesting that AM is essential for vascular morphogenesis. AM activates the PI3K/Akt-dependent pathway in vascular endothelial cells (58), which is considered to regulate multiple critical steps in angiogenesis, including endothelial cell survival, proliferation, migration, and capillary-like structure formation (27). These findings raise the possibility that AM plays a role in modulating angiogenesis and neovascularization. This review focused on the angiogenic effects of AM and the therapeutic potential of AM gene transfer for the treatment of intractable cardiovascular disease.


   ENDOGENOUS AM PRODUCTION IN ISCHEMIC CONDITIONS
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 ENDOGENOUS AM PRODUCTION IN...
ANGIOGENIC EFFECTS OF AM...
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Hypoxia (14, 53) and cytokine production (73) in ischemic heart disease or septic shock, as well as shear stress (7) in hypertension and heart failure induce AM secretion by vascular cells (Fig. 1). We have shown that plasma AM level is increased in patients with acute myocardial infarction (40, 49), peripheral arterial occlusive disease (75), and congestive heart failure (28, 55). Tissue levels of AM peptide and mRNA are also markedly increased in ischemic myocardium (18, 50) and failing heart (8, 56, 78, 82). These findings suggest that expression of AM is upregulated under tissue ischemia and inflammation, both of which are associated with neovascularization. An in vitro study has demonstrated that AM is upregulated through a hypoxia-inducible factor-1 (HIF-1)-dependent pathway under hypoxic conditions (14). Thus hypoxia/HIF-1 is one of the most potent regulators of AM production (Fig. 1). A recent study has demonstrated that heterozygous AM knockout mice [AM(+/–)] show significantly less blood flow recovery with less collateral capillary development than their wild-type mice (20). Administration of AM promotes blood flow recovery and capillary formation in AM(+/–) mice. These findings suggest that endogenous AM may play an important role in the regulation of angiogenesis under ischemic conditions. Considering the angiogenic potency of AM, increased endogenous AM represents a compensatory mechanism as an angiogenic factor promoting neovascularization under hypoxic conditions.



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  		Fig. 1. Signaling pathway of adrenomedullin (AM) in vascular endothelial cells and smooth muscle cells. Both AM and calcitonin-receptor-like receptor (CRLR) are upregulated through a, hypoxia-inducible factor-1 (HIF-1)-dependent pathway under hypoxic conditions. AM binds to CRLR modified by receptor-activity-modifying protein 2 (RAMP2) and RAMP3. AM induces angiogenesis through activation of Akt, MAPK, and p125FAK in endothelial cells. AM also induces SMC migration and vasodilation. These activities synergistically improve tissue ischemia. MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; ERK, extracellular signal-regulated kinase; PI3K, phosphatidylinositol 3-kinase; p125FAK, focal adhesion kinase; PLC, phospholipase C; PI, phosphatidylinositol; IP3, inositol triphosphate; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; cGMP, guanosine 3',5'-cyclic monophosphate; PKG, protein kinase G; PKA, protein kinase A.

 

   ANGIOGENIC EFFECTS OF AM AND ITS SIGNALING PATHWAY
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 ENDOGENOUS AM PRODUCTION IN...
 ANGIOGENIC EFFECTS OF AM...
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AM signaling is of particular significance in endothelial cell biology since the peptide protects cells from apoptosis (31), promotes angiogenesis (35, 60), and affects vascular tone (23). Angiogenesis is a multistep process that involves migration and proliferation of endothelial cells, functional maturation of the newly assembled vessels, and remodeling of the extracellular matrix (26). Akt, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2), and focal adhesion kinase (p125FAK) play an important role in angiogenesis in endothelial cells. Kim et al. (35) demonstrated that AM activated Akt, MAPK/ERK1/2, and p125FAK in human umbilical vein endothelial cells (HUVECs), and produced increases in their DNA synthesis and migration. AM induced tube formation in HUVECs, and its effect was inhibited by pretreatment with a phosphatidylinositol 3'-kinase (PI3K) inhibitor or mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)1/2 inhibitor. These findings suggest that AM exerts angiogenic activities through activation of Akt, MAPK, and p125FAK in endothelial cells (Fig. 1). In vivo, overexpression of AM augments collateral flow in ischemic tissues partly through activation of endothelial nitric oxide synthase (eNOS) (1). Earlier studies have shown that the vasodilatory effects of AM are mediated by cAMP/protein kinase in smooth muscle cells (SMCs) (23) and by the eNOS/NO pathway in endothelial cells (17). Thus AM-induced angiogenesis and vasodilation may synergistically improve blood perfusion in ischemic tissues.

Recently, a seven-transmembrane G-protein-coupled receptor, calcitonin receptor-like receptor (CRLR), and receptor activity modifying proteins (RAMPs) have been recognized as integral components of the AM signaling system (38, 43). CRLR has demonstrated the expression of the transcript predominantly in microvascular endothelial cells. This finding supports the view that CRLR is potentially a major mediator of the effects of AM on the vasculature. The effect of AM on CRLR is modified by RAMP2 and RAMP3. The angiogenic effect of AM is mediated by CRLR/RAMP2 and CRLR/RAMP3 receptors (Fig. 1). VEGF and AM act synergistically to induce angiogenic-related effects on endothelial cells in vitro (11). However, blocking antibodies to VEGF cannot significantly inhibit AM-induced capillary tube formation by HUVECs, indicating that AM does not function indirectly through upregulation of VEGF. Interestingly, AM and CRLR are both upregulated under hypoxic conditions in microvascular endothelial cells, although expression of RAMPs is not activated by hypoxia in microvascular cells (54). The activity of the CRLR promoter under hypoxic conditions is regulated at least in part through hypoxia-responsive regulatory element binding transcription factor HIF-1. Thus the simultaneous transcriptional upregulation of CRLR and its ligand AM in endothelial cells might play a significant role in the vascular responses to hypoxia and ischemia by creating a potent survival loop.

SMCs are essential for the generation of functional and mature blood vessels (26). We demonstrated in vivo that intramuscular administration of AM increased the number of {alpha}SMA-positive cells involved in the formation of vascular structures (25). In vitro, AM enhanced SMC migration, which was inhibited by wortmannin, a PI3K inhibitor. Recent studies using homozygous AM knockout mice have suggested that AM is essential for vascular morphogenesis (6, 21, 70). Taking these findings together, it is possible that AM contributes to vessel maturation through enhancement of SMC migration via a PI3K/Akt-dependent pathway (Fig. 1). This feature of AM-induced angiogenesis is different from VEGF-induced angiogenesis, which is not associated with vessel muturation.

In tumor cells, inflammation and hypoxia increase AM expression, and the elevated expression of AM is associated with tumor neovascularization in xenografted endometrial tumors and renal cell carcinoma (12, 86). AM also acts as a tumor cell survival factor underlying human carcinogenesis. Thus hypoxia-induced AM plays a part in tumor angiogenesis in conjunction with VEGF, and facilitates tumor growth under hypoxic conditions. As angiogenesis is an essential process in tumor-host interactions for tumor growth, maintenance, and metastasis, finding ways to regulate the action of AM may provide a new avenue for developing anticancer therapy (16).


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 ENDOGENOUS AM PRODUCTION IN...
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A variety of studies have demonstrated that AM gene delivery serves as therapeutic tool to protect the cardiovascular system, including the heart (9, 32, 85), kidney (83), and vasculature (2, 84). In this section, we describe the angiogenic potential of AM gene transfer using novel gene delivery systems.

Nonviral gene transfer. Peripheral vascular disease is a crucial health issue affecting an estimated 27 million people (5). Despite recent advances in medical interventions, the symptoms of some patients with critical limb ischemia fail to be controlled. Although gene therapy has been shown to be an effective approach for angiogenesis (10, 24, 72), it is still unsatisfactory because of the biohazard of viral vectors, low transfection efficiency, and premature tissue-targeting. Therefore, highly efficient and safe gene transfer is desirable. Recently, we developed a novel nonviral vector, gelatin hydrogel, which allows highly efficient and long-lasting gene transfer (13, 30, 81). Gelatin has been widely used as a carrier of protein because of its capacity to delay protein degradation (76, 77). Plasmid DNA is known to be negatively charged. Thus we used gelatin as a vector for gene therapy. Biodegradable gelatin was prepared from pig skin. The gelatin was characterized by a spheroid shape with a diameter of ~30 µm, water content of 95% and an isoelectric point of 9 after swelling in water (76, 77). After 2-h incubation, positively charged gelatin held negatively charged plasmid DNA in its positively charged lattice structure. DNA particles are released from the gelatin through its degradation. As a result, DNA-gelatin complexes can delay gene degradation, leading to efficient gene transfer (13, 30, 44, 81).

We examined whether nonviral vector gelatin-mediated AM gene transfer induces therapeutic angiogenesis in a rabbit model of hindlimb ischemia (81). Seven days after intramuscular injection of AM DNA-gelatin complexes, there was intense AM immunoreactivity surrounding the gelatin in the skeletal muscles. AM production in the AM-gelatin group was enhanced compared with that in the naked AM DNA group, which received plasmid AM DNA alone. Unlike AM production in the naked AM group, AM overexpression in the AM-gelatin group lasted for longer than 2 wk. Importantly, AM DNA-gelatin complexes induced more potent angiogenic effects in a rabbit model of hindlimb ischemia than naked AM DNA, as evidenced by significant increases in histological capillary density, calf blood pressure ratio, and laser Doppler flow. These results suggest that the use of biodegradable gelatin as a nonviral vector augments AM expression and enhances AM-induced angiogenic effects. AM DNA-gelatin complexes were distributed mainly in connective tissues. It is interesting to speculate that the delay of gene degradation by gelatin may have been responsible for the highly efficient gene transfer. Thus gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of severe peripheral vascular disease.

Cell-based gene transfer. Recently, transplantation of stem cells or progenitor cells has been shown to regenerate a variety of tissues. Endothelial progenitor cells (EPCs) have been discovered in adult peripheral blood (4, 79). EPCs are mobilized from bone marrow into the peripheral blood in response to tissue ischemia or traumatic injury, migrate to sites of injured endothelium, and differentiate into mature endothelial cells in situ (15, 34). Transplantation of EPC induces therapeutic angiogenesis in the ischemic heart or limb (34, 42, 71). However, some patients are refractory to conventional cell therapy because of insufficient cell number, poor survival, or impaired differentiation. Thus a novel therapeutic strategy to enhance the angiogenic properties of EPCs is desirable. Considering the variety of protective effects of AM on vascular endothelial cells, we hypothesized that AM gene transfer into EPCs would strengthen the therapeutic potential of EPCs. Genetically modified EPCs may serve not only as a tissue-engineering tool to reconstruct the vasculature but also as a vehicle for gene delivery to injured endothelium.

Here, we present a new concept for cell-based gene delivery into the vasculature, consisting of three processes (44). First, positively charged gelatin is readily complexed with negatively charged plasmid DNA. Second, EPCs phagocytose ionically linked plasmid DNA-gelatin complexes in coculture, which allows nonviral gene transfer into EPCs with high efficiency. Third, intravenously administered gene-modified EPCs are incorporated into injured vascular beds. This novel gene delivery system has great advantages over conventional gene therapy; it is nonviral and noninvasive, and it provides highly efficient gene targeting into the vasculature. These benefits may be achieved mainly by the capability of EPCs to phagocytose DNA-gelatin complexes and to migrate to sites of injured endothelium. Genetically modified EPCs markedly secreted AM into the culture medium, and AM overproduction lasted for more than 2 wk. The proliferative activity of AM DNA-transduced EPCs exceeded that of nontransduced EPCs. Furthermore, AM gene transfer inhibited apoptosis of EPCs in vivo and in vitro. Thus ex vivo AM gene transfer strengthened the therapeutic potential of EPCs.

Primary pulmonary hypertension (PPH) is a rare, but life-threatening disease characterized by progressive pulmonary hypertension, ultimately producing right ventricular failure and death (67). Median survival in patients with PPH is considered to be 2.8 years from the time of diagnosis. Thus novel and effective therapy is needed for the treatment of pulmonary hypertension. Because endothelial dysfunction may play a role in the pathogenesis of pulmonary hypertension such as PPH (3), pulmonary endothelial cells may be a therapeutic target for the treatment of pulmonary hypertension. We have demonstrated that administration of AM peptide decreases pulmonary vascular resistance in patients with PPH (45, 46, 48, 51). Thus we investigated the effects of AM gene-modified EPCs on pulmonary hypertension in rats (44). AM gene-transduced EPCs were similarly incorporated into the pulmonary vasculature. Immunohistochemical analyses demonstrated that the transplanted EPCs were of endothelial lineage and formed vascular structures. Intravenous administration of AM-expressing EPCs significantly decreased pulmonary vascular resistance compared with EPCs alone (–39%). Kaplan-Meier survival curves demonstrated that rats with pulmonary hypertension transplanted with AM-expressing EPCs had a significantly higher survival rate than those given culture medium or EPCs alone. These findings suggest that AM gene-modified EPCs using gelatin may serve not only as a tissue-engineering tool to reconstruct the pulmonary vasculature, but also as a vehicle for gene delivery to injured pulmonary endothelium. This hybrid cell-gene therapy may be applicable for intractable cardiovascular disease, including ischemic heart disease. Thus genetic manipulation of stem cells opens new avenues for regenerative medicine.


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 ENDOGENOUS AM PRODUCTION IN...
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This work was supported by the Research Grant for Cardiovascular Disease (16C-6) from the Ministry of Health, Labor and Welfare, Industrial Technology Research Grant Program in 2003 from New Energy and Industrial Technology Development Organization of Japan, Health and Labor Sciences Research Grants-Genome 005, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research of Japan.


   FOOTNOTES
 

Address for reprint requests and other correspondence: Noritoshi Nagaya, Dept. of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan (E-mail: nnagaya{at}ri.ncvc.go.jp)


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