Published online before print December 31, 2001, doi: 10.1161/hc0602.103673
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(Circulation. 2002;105:732.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Endothelial Progenitor Cell Vascular Endothelial Growth Factor Gene Transfer for Vascular Regeneration
From the Division of Cardiovascular Research and Medicine (H.I., J.Y., C.K., S.M., H.M., S.H., M.S., T.L., J.M.I., T.A.), St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass; and the Department of Physiology (H.I.) and Institute of Medical Science (T.A.), Tokai University School of Medicine, Japan.
Correspondence to Takayuki Asahara, MD, PhD, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA, 02135. E-mail asa777{at}aol.com
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Abstract |
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Background— Previous studies have established that bone marrow–derived endothelial progenitor cells (EPCs) are present in the systemic circulation. In the current study, we investigated the hypothesis that gene transfer can be used to achieve phenotypic modulation of EPCs.
Methods and Results— In vitro, ex vivo murine vascular endothelial growth factor (VEGF) 164 gene transfer augmented EPC proliferative activity and enhanced adhesion and incorporation of EPCs into quiescent as well as activated endothelial cell monolayers. To determine if such phenotypic modulation may facilitate therapeutic neovascularization, heterologous EPCs transduced with adenovirus encoding VEGF were administered to athymic nude mice with hindlimb ischemia; neovascularization and blood flow recovery were both improved, and limb necrosis/autoamputation were reduced by 63.7% in comparison with control animals. The dose of EPCs used for the in vivo experiments was 30 times less than that required in previous trials of EPC transplantation to improve ischemic limb salvage. Necropsy analysis of animals that received DiI-labeled VEGF-transduced EPCs confirmed that enhanced EPC incorporation demonstrated in vitro contributed to in vivo neovascularization as well.
Conclusions— In vitro, VEGF EPC gene transfer enhances EPC proliferation, adhesion, and incorporation into endothelial cell monolayers. In vivo, gene-modified EPCs facilitate the strategy of cell transplantation to augment naturally impaired neovascularization in an animal model of experimentally induced limb ischemia.
Key Words: gene therapy • endothelium • angiogenesis • ischemia
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Introduction |
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Previous studies from our laboratory1–6 and others7–13 have established that bone marrow–derived endothelial progenitor cells (EPCs) are present in the systemic circulation, are augmented in response to certain cytokines and/or tissue ischemia, and home to as well as incorporate into sites of neovascularization. More recently, EPCs have been investigated as therapeutic agents; in these studies of "supply-side angiogenesis," EPCs harvested from the peripheral circulation have been expanded ex vivo and then administered to animals with limb14 or myocardial15 ischemia to successfully enhance neovascularization. Physiological evidence of neovascular function in these preclinical animal models includes a high rate of limb salvage and improvement in myocardial function.
See p 672
EPC transplantation thus constitutes a novel therapeutic strategy that could provide a robust source of viable endothelial cells (ECs) to supplement the contribution of ECs resident in the adult vasculature that migrate, proliferate, and remodel in response to angiogenic cues, according to the classic paradigm of angiogenesis developed by Folkman and colleagues.16 Just as classic angiogenesis may be impaired in certain pathological phenotypes,17–20 however, aging, diabetes, hypercholesterolemia, and hyperhomocysteinemia may likewise impair EPC function, including mobilization from the bone marrow and incorporation into neovascular foci. Gene transfer of EPCs during ex vivo expansion constitutes a potential means of addressing such putative liabilities in EPC function. Moreover, phenotypic modulation of EPCs ex vivo may also reduce the number of EPCs required for optimal transplantation after ex vivo expansion and thus serve to address a practical limitation of EPC transplantation, namely the volume of blood required to extract an optimal number of EPCs for autologous transplantation.
Accordingly, we investigated the hypothesis that gene transfer can be used to achieve phenotypic modulation of EPCs. In particular, we sought to determine the impact of vascular endothelial growth factor (VEGF) gene transfer on certain properties of EPCs in vitro and the consequences of VEGF EPC-gene transfer on neovascularization in vivo.
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Methods |
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EPC Culture
Ex vivo expansion of EPC was performed as recently described.14 In brief, peripheral blood mononuclear cells from human volunteers were plated on human fibronectin–coated (Sigma) culture dishes and maintained in EC basal medium-2 (EBM-2) (Clonetics) supplemented with 5% fetal bovine serum, human VEGF-A, human fibroblast growth factor-2, human epidermal growth factor, insulin-like growth factor-1, and ascorbic acid. After 4 days in culture, nonadherent cells were removed by washing, new media was applied, and the culture maintained through day 7.
EPC Gene Transfer
After 7 days in culture, cells were transduced with an adenovirus encoding the murine VEGF 164 gene (Ad/VEGF) or lacZ gene (Ad/ßgal) (generously provided by Kevin Peters).21 To establish optimum conditions for EPC adenovirus gene transfer serum concentration, virus incubation time and virus concentration were evaluated (Figure 1). After preliminary experiments were performed, human EPCs were transduced with 1000 MOI Ad/VEGF or Ad/ßgal for 3 hours in 1% serum media. After transduction, cells were washed with PBS and incubated with EPC media for 24 hours before transplantation.
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Proliferative Activity Assay
At 24 hours after gene transfer, EPCs transduced with Ad/VEGF (Td/V-EPCs), Ad/ß-gal (Td/ß-EPCs), or nontransduced EPCs (non-Td/EPCs) were reseeded on 96-well plates coated with human fibronectin for assay of proliferative activity with the use of the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] Assay (Promega). After 48 hours in culture, MTS/PMS (phenazine methosulfate) solution was added to each well for 3 hours, and light absorbance at 490 nm was detected by ELISA plate reader (Bionetics Laboratory).
In Vitro Incorporation of Td-EPCs Into Human Umbilical Vein Endothelial Cell Monolayer
At 24 hours after gene transfer, Td/V-EPCs and Td/ß-EPCs were stained with fluorescent carbocyanine DiI (Biomedical Technologies). DiI-labeled EPCs were incubated on a monolayer of human umbilical vein endothelial cells (HUVECs) in 4-well culture slides with or without pretreatment of tumor necrosis factor (TNF)-
(1ng/mL) for 12 hours.22 Three hours after incubation, nonadherent cells were removed by washing with PBS, new media was applied, and the culture was maintained for an additional 24 hours. The total number of adhesive EPCs in each well was counted in a blinded manner under a x200 magnification field of a fluorescent microscope.
Td-EPCs Transplantation Animal Model
All procedures were performed in accordance with the St Elizabeth’s Institutional Animal Care and Use Committee. Female athymic nude mice (Jackson Laboratory, Bar Harbor, Maine), 8 to 9 weeks old and 17 to 20 g weight, were anesthetized with 160 mg/kg IP pentobarbital for operative resection of one femoral artery23 and subsequently for laser Doppler perfusion imaging.
As a preliminary experiment, we performed dose-dependent EPC transplantation to determine the minimum number of VEGF-transduced EPCs that was required to achieve a magnitude of therapeutic neovascularization similar to that which could be achieved with nontransduced EPCs. According to this result, 1.5x104 VEGF-transduced EPCs, 30 times less than the number required for cell therapy alone, were used in the current series of in vivo experiments. One day after unilateral femoral artery excision, 1.5x104 Td/V-EPCs (n=11), Td/ß-EPCs (n=11), or non-Td/EPCs (n=5) in 100 µL EBM-2 media without growth factors were administered through the tail vein.
To track the fate of transplanted EPCs, 4 mice in each EPC cohort received EPCs that were marked with the fluorescent carbocyanine DiI dye (Molecular Probes). In brief, before cellular transplantation, EPCs in suspension were washed with PBS and incubated with DiI at a concentration of 2.5 µg/mL PBS for 5 minutes at 37°C and 15 minutes at 4°C. After two washing steps in PBS, the cells were resuspended in EBM-2 medium. At 30 minutes before the animals were killed, a subgroup (n=4 each group) of mice received an intravenous injection of 50 µg of Bandeiraea simplicifolia lectin 1 (BS-1) conjugated with FITC (Vector Laboratories).
Plasma VEGF Levels
To confirm that the Ad/VEGF could mediate successful gene transfer at the protein level, an enzyme-linked immunoassay (ELISA, R&D System) was used to quantify VEGF levels in plasma from animals 1, 4, 7, and 28 days after intravenous injections of Td/V-EPCs or Td/ß-EPCs. The results were compared with a standard curve constructed with murine VEGF (each assay carried out in duplicate for each animal). Absorbance was measured at 450 nm by means of a microplate reader.
Physiological Assessment of Animals Given Transplantation
Laser Doppler perfusion imaging (LDPI) (Moor Instruments) was used to record blood flow measurements on day 0 and day 28 after surgery, as previously described. In these digital color-coded images, red hue indicates regions with maximum perfusion, medium perfusion values are shown in yellow, and lowest perfusion values are represented as blue. The resulting images display absolute values in readable units. For quantification, the ratio of readable units in ischemic to nonischemic hindlimb is determined.
Histological Assessment of Animals Given Transplantation
Vascular density was evaluated at the microvascular level through the use of light microscopic sections harvested from the ischemic hindlimbs at necropsy. Tissue sections from the lower calf muscles of ischemic limbs were harvested on days 7 and 28. Muscle samples were embedded in OCT compound (Miles), snap-frozen in liquid nitrogen, and cut into 5-µm-thick sections. Tissue sections were stained for alkaline phosphatase with an indoxyltetrazolium method to detect capillary endothelial cells as previously described23 and then were counterstained with eosin. A total of 20 different fields were randomly selected, and the number of capillaries and myofibers were counted (x40 magnification for 20 fields).
Statistical Analysis
All results are expressed as mean±SEM. Statistical significance was evaluated by means of a paired Scheffé t test or ANOVA. A value of P<0.05 was considered to denote statistical significance.
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Results |
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Proliferative Activity Assay
MTS assay was used to determine proliferative activity of transduced EPCs. With the use of 5% serum-conditioned media, proliferative activity of Ad/VEGF-transduced EPCs exceeded proliferative activity of Ad/ß-gal (0.48±0.03 versus 0.37±0.01 corrected absorbance at 490 nm, P<0.01) and nontransduced EPCs (non-Td=0.32±0.02, P<0.05) in vitro (Figure 2).
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In Vitro Incorporation of Td-EPCs Into HUVEC Monolayer
At 24 hours after transduction, EPCs were labeled with the fluorescent marker DiI for cell tracking. DiI-labeled, VEGF-transduced EPCs were incubated on a HUVEC monolayer with or without TNF- (1 ng/mL) pretreatment for 12 hours (Figure 3A). After 3 hours of incubation, nonadherent cells were removed by washing with PBS, and DiI-marked cells adherent to the HUVEC monolayer were manually counted. In the quiescent HUVEC monolayer, adhesion of DiI-labeled EPCs was not significantly different between Td/V-EPCs and Td/ß-EPC (2.7±0.2 versus 2.2±0.3, P=NS) (Figure 3B). In activated HUVECs, however, adhesion of DiI-labeled Td/V-EPCs exceeded Td/ß-EPCs (4.3±0.4 versus 2.9±0.3, P<0.01).
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Alternatively, the same cells were incubated in new media and maintained for 24 hours on the HUVEC monolayer to confirm incorporation in vitro. In the quiescent HUVEC monolayer, incorporation of DiI-labeled Td/V-EPCs exceeded Td/ß-EPCs (7.0±0.5 versus 3.5±0.5, P<0.01) (Figure 3B). In activated HUVECs, incorporation of DiI-labeled Td/V-EPCs also exceeded Td/ß-EPCs (13.8±0.8 versus 5.3±0.6, P<0.001).
Transgene Expression After Td/V-EPC Transplantation
Ad/VEGF-mediated gene transfer and expression were confirmed by ELISA assay of plasma samples obtained from mice after Td/V-EPC transplantation. Mice transplanted with Td/V-EPCs disclosed significantly higher VEGF protein levels (day 1, 828.18±8.84 versus 4.56±2.21 pg/mL; day 4, 421.27±12.60 versus 5.16±2.79 pg/mL; day 7, 65.65±3.20 versus 3.78±2.26 pg/mL; day 28, 17.40±1.99 versus 4.42±1.88 pg/mL; P<0.01) at each time point than did mice transplanted with Td/ß-EPCs (Figure 4).
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EPC Incorporation Into Ischemic Hindlimb
Transplanted human EPC derived cells marked with DiI were identified in tissue sections by red fluorescence. In contrast, the mouse vasculature, stained by premortem administration of BS-1 lectin, was identified by green fluorescence in the same tissue sections. Td/V-EPC–transplanted animals disclosed increased numbers of DiI-labeled, red fluorescent EPC–derived vasculature as well as mouse vasculature versus control groups (Td/ß-EPC and non-Td group) (Figure 5A).
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Both transplanted EPC-derived vasculature and mouse vasculature were analyzed quantitatively in the same microscopic field. The density of DiI-labeled EPCs in tissue sections of hindlimb muscles was greater in the Td/V-EPC group (389±23 mm2) than either of the other two groups (non-Td/EPCs=241±18 mm2; Td/ß-EPCs=236±20 mm2, P<0.001) at day 7 (Figure 5B). The density of BS-1 lectin–positive vasculature in sections of skeletal muscle removed from the ischemic limb was also greater in the Td/V-EPC group (391±16 mm2) than the other two groups (non-Td/EPCs=263±18 mm2; Td/ß-EPCs=292±26 mm2, P<0.01) at day 7 (Figure 5C).
Physiological Assessment of Animals Given Transplantation
The impact of human gene–modified EPC administration on neovascularization was investigated in a murine model of hindlimb ischemia. One day after operative excision of one femoral artery, athymic nude mice (n=27), in which angiogenesis is characteristically impaired,14,21 received an intravenous injection of 1.5x104 transduced EPCs (Td/V-EPCs, n=11) or Td/ß-EPCs (n=11). As additional control animals, 5 mice with hindlimb ischemia were identically injected with non-Td/EPCs. Enhanced neovascularization in mice transplanted with Td/V-EPCs led to important biological consequences, compared with control animals.
After administration of Td/ß-EPCs to 11 mice, 3 (27.2%) had extensive toe necrosis, and the remaining 8 (72.7%) underwent autoamputation of the ischemic limb (Figure 6A). In contrast, Td/V-EPC transplantation was associated with successful limb salvage in 7 (63.6%) of 11 animals; toe necrosis was limited to 3 (27.2%) mice, and only 1 (9%) had spontaneous limb amputation (Figure 6B).
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Serial examination of hindlimb perfusion by LDPI was performed at days 0 and 28 (Figure 7A). The ratio of ischemic/normal blood flow in mice transplanted with Td/V-EPCs indicated significantly greater hindlimb perfusion compared with those mice transplanted with Td/ß-EPCs and nontransduced EPCs at day 28 (0.71±0.15 versus 0.40±0.03 versus 0.34±0.04, P<0.05) (Figure 7B).
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Histological Assessment of Animals Given Transplantation
To further evaluate the impact of EPC gene transfer on revascularization of the ischemic hindlimb, histological examination of skeletal muscle sections retrieved from the ischemic hindlimbs of mice killed at day 28 was performed as described above. Capillary density observed in the mice transplanted with Td/V-EPCs was significantly higher than in mice receiving Td/ß-EPCs (421±15 versus 230±14/mm2, P<0.05) or nontransduced mice EPCs (183±16/mm2, P<0.05) (Figure 8). Similarly, the capillary/muscle fiber ratios in the Ad/VEGF transplanted mice were significantly higher than in Td/ß-EPCs or non-Td/EPCs transplanted mice (0.62±0.02 versus 0.39±0.03 versus 0.35±0.05, P<0.01).
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Discussion |
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The finding that circulating EPCs may home to sites of neovascularization and differentiate into ECs in situ is consistent with "vasculogenesis,"24 a critical paradigm for establishment of the primordial vascular network in the embryo. Although the proportional contributions of angiogenesis and vasculogenesis to postnatal neovascularization remain to be clarified, our findings together with the recent reports from other investigators7–13 suggest that growth and development of new blood vessels in the adult are not restricted to angiogenesis but encompass both embryonic mechanisms. As a corollary, augmented or retarded neovascularization—whether endogenous or iatrogenic—probably includes enhancement or impairment of vasculogenesis.
Therapeutic Vasculogenesis
We therefore considered a novel strategy of EPC transplantation to provide a source of robust ECs that might supplement fully differentiated ECs thought to migrate and proliferate from preexisting blood vessels according to the classic paradigm of angiogenesis developed by Folkman and colleagues.16 Our studies indicated that ex vivo cell therapy, consisting of culture-expanded EPC transplantation, successfully promotes neovascularization of ischemic tissues, even when administered as "sole therapy," for example, in the absence of angiogenic growth factors.
Such a "supply side" version of therapeutic neovascularization in which the substrate rather than ligand comprises the therapeutic agent was first demonstrated in a immune deficient murine model of hindlimb ischemia, with the use of donor cells from human volunteers.14 These findings provided novel evidence that exogenously administered EPCs augment naturally impaired neovascularization in an animal model of experimentally induced critical limb ischemia. Not only did heterologous cell transplantation improve neovascularization and blood flow recovery, but important biological consequences—notably limb necrosis and autoamputation—were reduced by 50% in comparison with mice receiving differentiated ECs or control mice receiving media in which harvested cells were expanded ex vivo before transplantation.
More recently, this same strategy has been used successfully to enhance myocardial function after myocardial infarction in experimental animal models as well.15 Peripheral blood mononuclear cells obtained from healthy human adults were cultured in EPC medium, harvested 7 days later, and administered intravenously to Hsd:RH-rnu (athymic nude) rats with myocardial ischemia induced by ligation of the left anterior descending coronary artery. Fluorescent microscopy of DiI-labeled EPCs revealed that transplanted EPCs accumulated to the ischemic area and incorporated into foci of myocardial neovascularization. Echocardiography disclosed ventricular dimensions that were significantly smaller and fractional shortening that was significantly greater in the EPC versus control animals. Necropsy examination disclosed that capillary density was significantly greater and the extent of left ventricular scarring was significantly less in rats receiving EPCs versus control animals.
Logistics of Primary EPC Transplantation
Despite promising potential for regenerative applications, the fundamental scarcity of EPC populations in the hematopoietic system, combined with possible functional impairment of EPCs associated with a variety of phenotypes such as aging, diabetes, hypercholesterolemia, and homocysteinemia,17–20 constitute important limitations of primary EPC transplantation. Ex vivo expansion of EPCs cultured from the peripheral blood of healthy human volunteers typically yields 
5.0x106 cells per 100 mL of blood. Our animal studies14 suggest that heterologous transplantation requires 0.52.0x104 human EPCs/grams of weight (of the recipient mouse) to achieve satisfactory reperfusion of the ischemic hindlimb.
Rough extrapolation of this experience to humans suggests that a volume of as much as 12 L of peripheral blood may be necessary to harvest the EPCs required to treat critical limb ischemia. Even with the integration of certain technical improvements, the adjustment of species compatibility by autologous transplantation, and adjunctive strategies (eg, cytokine supplements) to promote EPC mobilization,3,4 the primary scarcity of a viable and functional EPC population constitutes a potential liability of therapeutic vasculogenesis based on the use of ex vivo expansion alone.
Advantage of VEGF EPC Gene Transfer
Our current findings provide the first evidence that exogenously administered, gene-modified EPCs augment naturally impaired neovascularization in an animal model of experimentally induced limb ischemia. Previous studies from our laboratory14,21 established that neovascularization is impaired in nude rodents; failure of a satisfactory endogenous response to limb ischemia leads to extensive necrosis, including limb autoamputation, in nearly all animals. Transplantation of heterologous EPCs transduced with adenovirus encoding VEGF improved not only neovascularization and blood flow recovery but also had meaningful biological consequences: Limb necrosis and autoamputation were reduced by 63.7% in comparison with control animals.
The dose of EPCs used in the current in vivo experiments was subtherapeutic; that is, this dose of EPCs was 30 times less than that required in previous experiments to improve the rate of limb salvage above that seen in untreated control animals. Adenoviral VEGF EPC gene transfer, however, accomplished a therapeutic effect, as evidenced by a functional outcome, despite a subtherapeutic dose of EPCs. Thus, VEGF EPC gene transfer constitutes one option to address the limited number of EPCs that can be isolated from peripheral blood before ex vivo expansion and subsequent autologous readministration.
The results of our in vitro studies provide potential insights into the mechanisms responsible for the in vivo outcomes. First, VEGF gene transfer augmented EPC proliferative activity. Second, VEGF gene transfer enhanced adhesion and incorporation of EPCs into a quiescent endothelial cell monolayer as well as ECs activated by pretreatment with TNF-. These findings suggest that modulation of adhesion molecule expression after VEGF gene transfer may promote homing of EPCs to foci of ischemia and are consistent with previous studies demonstrating VEGF-induced upregulation of certain EC integrins and matrix proteins.25 Given that EPCs by definition express VEGF receptors, the potential for autocrine effects—demonstrated previously by our laboratory for ECs26—on proliferation, migration, and possibly survival of EPCs probably contributed to the reduced requirement of harvested EPCs.
Given the ELISA results demonstrating increased levels of VEGF protein in animals that received VEGF-transduced EPCs, it is also likely that indirect effects of VEGF transduction contributed to improved limb neovascularity. Because ex vivo–expanded EPCs are preferentially recruited to ischemic foci for neovascularization,14,15 EPCs may operate as a Trojan horse, promoting local overexpression of secreted VEGF that may in turn promote migration, proliferation, and remodeling of differentiated ECs resident in the target ischemic tissue. The extent to which augmented neovascularity derives from phenotypically modified EPCs versus enhanced proliferation and migration of native ECs in response to VEGF secreted from transduced EPCs is difficult to discern because of the lack of valid methods available to quantify local VEGF overexpression.
Furthermore, it must be acknowledged that the possibility of similar outcomes achieved with non-EPC circulating cells that overexpress VEGF (or a combination of VEGF-expressing non-EPCs administered together with nontransduced EPCs) has not been excluded by the current studies. Testing such alternative approaches, however, is currently precluded by the lack of non-EPC cells that can (a) be ex vivo–transduced with equal efficiency; (b) circulate in vivo for some reasonable time period; and (c) be recruited to as well as incorporate into foci of neovascularization.
Vector-Specific Issues
Transient gene expression is characteristic of adenoviral vectors.27 For purposes of therapeutic neovascularization, this feature is unlikely to constitute a liability, given the plethora of previous preclinical and clinical studies suggesting that VEGF overexpression for 4 weeks or less, whether achieved by transfer of naked plasmid DNA28–31 or use of an adenoviral vector,32,33 is sufficient to augment angiogenesis. Indeed, previous work by others has demonstrated that protracted VEGF overexpression may result in hemangioma formation in normal skeletal muscle34 as well as myocardium.35 This potential complication was not observed in the experiments described herein.
The potential for immunologic complications remains a concern attached to the use of adenoviral vectors, despite certain reports to the contrary.33 In the current application, however, the ex vivo transduction strategy used may preclude exposure of the adenovirus to the immune system of the transplant recipients. Thus, administration of the transgene by ex vivo viral gene transfer may not detract from the safety of this application for clinical gene therapy.
Received October 12, 2001; revision received November 29, 2001; accepted December 14, 2001.
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References |
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1. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997; 275: 964–967.
2. Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999; 85: 221–228.
3. Takahashi T, Kalka C, Masuda H, et al. Ischemia-, and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999; 5: 434–438.
4. Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J. 1999; 18: 3964–3972.
5. Kalka C, Masuda H, Takahashi T, et al. Vascular endothelial growth factor165 gene transfer augments circulating endothelial progenitor cells in human subjects. Circ Res. 2000; 86: 1198–1202.
6. Kalka C, Tehrani H, Laudenberg B, et al. Mobilization of endothelial progenitor cells following gene therapy with VEGF165 in patients with inoperable coronary disease. Ann Thorac Surg. 2000; 70: 829–834.
7. Shi Q, Rafii S, Wu MH-D, et al. Evidence for circulating bone marrow-derived endothelial cells. Blood. 1998; 92: 362–367.
8. Hatzopoulos AK, Folkman J, Vasile E, et al. Isolation and characterization of endothelial progenitor cells from mouse embryos. Development. 1998; 125: 1457–1468.
9. Gunsilius E, Duba HC, Petzer AL, et al. Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells. Lancet. 2000; 355: 1688–1691.
10. Gehling UM, Ergun S, Schumacher U, et al. In vivo differentiation of endothelial cells from AC133-positive progenitor cells. Blood. 2000; 95: 3106–3112.
11. Crosby JR, Kaminski WE, Schatteman G, et al. Endothelial cells of hematopoietic origin make a significant contribution to adult blood vessel formation. Circ Res. 2000; 87: 728–730.
12. Moldovan NI, Goldschmidt-Clermont PJ, et al. Contribution of monocytes/macrophages to compensatory neovascularization: the drilling of metalloelastase-positive tunnels in ischemic myocardium. Circ Res. 2000; 87: 378–384.
13. Murohara T, Ikeda H, Duan J, et al. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest. 2000; 105: 1527–1536.
14. Kalka C, Masuda H, Takahashi T, et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A. 2000; 97: 3422–3427.
15. Kawamoto A, Gwon H-C, Iwaguro H, et al. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation. 2001; 103: 634–637.
16. Folkman J. Tumor angiogenesis.In: Holland JF, Frei EIII, Bast RC Jr, et al, eds. Cancer Medicine. 3rd ed. Philadelphia, Pa: Lea & Febiger; 1993: 153–170.
17. Gerhard M, Roddy M-A, Creager SJ, et al. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension. 1996; 27: 849–853.
18. Cosentino F, Luscher TF. Endothelial dysfunction in diabetes mellitus. J Cardiovasc Pharmacol. 1998; 32: S54–S61.
19. Drexler H, Zeiher AM, Meinzer K, et al. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by L-arginine. Lancet. 1991; 338: 1546–1550.
20. Luscher TF, Tshuci MR. Endothelial dysfunction in coronary artery disease. Annu Rev Med. 1993; 44: 395–418.
21. Couffinhal T, Silver M, Kearney M, et al. Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE-1- Mice. Circulation. 1999; 99: 3188–3198.
22. Simmons PJ, Masinovdky B, Longenecker BM, et al. Vascular cell adhesion molecule-1 expressed by bone marrow stromal cells mediates the binding of hematopoietic progenitor cells. Blood. 1992; 80: 388–395.
23. Couffinhal T, Silver M, Zheng LP, et al. A mouse model of angiogenesis. Am J Pathol. 1998; 152: 1667–1679.
24. Risau W, Sariola H, Zerwes H-G, et al. Vasculogenesis and angiogenesis in embryonic stem cell-derived embryoid bodies. Development. 1988; 102: 471–478.
25.
Senger DR, Ledbetter SR, Claffey KP, et al. Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the vß3 integrin, osteopontin, and thrombin. Am J Pathol. 1996; 149: 293–305.
26. Namiki A, Brogi E, Kearney M, et al. Hypoxia induces vascular endothelial growth factor in cultured human endothelial cells. J Biol Chem. 1995; 270: 31189–31195.
27. Watanabe T, Kusznyski C, Ino K, et al. Gene transfer into human bone marrow hematopoietic cells mediated by adenovirus vectors. Blood. 1996; 87: 5032–5039.
28. Losordo DW, Pickering JG, Takeshita S, et al. Use of the rabbit ear artery to serially assess foreign protein secretion after site specific arterial gene transfer in vivo: evidence that anatomic identification of successful gene transfer may underestimate the potential magnitude of transgene expression. Circulation. 1994; 89: 785–792.
29. Isner JM, Pieczek A, Schainfeld R, et al. Clinical evidence of angiogenesis following arterial gene transfer of phVEGF165. Lancet. 1996; 348: 370–374.
30. Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 following intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation. 1998; 97: 1114–1123.
31. Losordo DW, Vale PR, Symes J, et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation. 1998; 98: 2800–2804.
32. Mack CA, Patel SR, Schwarz EA, et al. Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart. J Thorac Cardiovasc Surg. 1998; 115: 168–176.
33. Giordano FJ, Ping P, McKirnan D, et al. Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nat Med. 1996; 2: 534–539.
34. Springer ML, Chen AS, Kraft PE, et al. VEGF gene delivery to muscle: potential role of vasculogenesis in adults. Mol Cell. 1998; 2: 549–558.
35. Lee RJ, Springer ML, Blanco-Bose WE, et al. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation. 2000; 102: 898–901.
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 A. D. Bhatwadekar, J. V. Glenn, T. M. Curtis, M. B. Grant, A. W. Stitt, and T. A. Gardiner Retinal Endothelial Cell Apoptosis Stimulates Recruitment of Endothelial Progenitor Cells Invest. Ophthalmol. Vis. Sci., October 1, 2009; 50(10): 4967 - 4973. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yamamoto, T. Matsuura, G. Narazaki, M. Sugitani, K. Tanaka, A. Maeda, G. Shiota, K. Sato, A. Yoshida, and I. Hisatome Synergistic effects of autologous cell and hepatocyte growth factor gene therapy for neovascularization in a murine model of hindlimb ischemia Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1329 - H1336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.-H. Huang, Y.-H. Chen, C.-H. Wang, J.-S. Chen, H.-Y. Tsai, F.-Y. Lin, W.-Y. Lo, T.-C. Wu, M. Sata, J.-W. Chen, et al. Matrix Metalloproteinase-9 Is Essential for Ischemia-Induced Neovascularization by Modulating Bone Marrow-Derived Endothelial Progenitor Cells Arterioscler Thromb Vasc Biol, August 1, 2009; 29(8): 1179 - 1184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Gulati and R. D. Simari Defining the potential for cell therapy for vascular disease using animal models Dis. Model. Mech., March 1, 2009; 2(3-4): 130 - 137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. I. Chang, R. G. Bonillas, S. El-ftesi, E. I. Chang, D. J. Ceradini, I. N. Vial, D. A. Chan, J. Michaels V, and G. C. Gurtner Tissue engineering using autologous microcirculatory beds as vascularized bioscaffolds FASEB J, March 1, 2009; 23(3): 906 - 915. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-P. T Ruifrok, R. A de Boer, A. Iwakura, M. Silver, K. Kusano, R. A Tio, and D. W Losordo Estradiol-induced, endothelial progenitor cell-mediated neovascularization in male mice with hind-limb ischemia Vascular Medicine, February 1, 2009; 14(1): 29 - 36. [Abstract] [PDF]
|
|
|
|
 |
|
 M. A. Sussman Showing up Isn't Enough for Vascularization: Persistence Is Essential Circ. Res., November 21, 2008; 103(11): 1200 - 1201. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Murasawa and T. Asahara Review: Cardiogenic potential of endothelial progenitor cells Therapeutic Advances in Cardiovascular Disease, October 1, 2008; 2(5): 341 - 348. [Abstract] [PDF]
|
|
|
|
 |
|
 E. Jabbarzadeh, T. Starnes, Y. M. Khan, T. Jiang, A. J. Wirtel, M. Deng, Q. Lv, L. S. Nair, S. B. Doty, and C. T. Laurencin Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: A combined gene therapy-cell transplantation approach PNAS, August 12, 2008; 105(32): 11099 - 11104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Penn and A. A. Mangi Genetic Enhancement of Stem Cell Engraftment, Survival, and Efficacy Circ. Res., June 20, 2008; 102(12): 1471 - 1482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C Kalka and I. Baumgartner Gene and stem cell therapy in peripheral arterial occlusive disease Vascular Medicine, May 1, 2008; 13(2): 157 - 172. [Abstract] [PDF]
|
|
|
|
 |
|
 T. Kinnaird, E. Stabile, S. Zbinden, M.-S. Burnett, and S. E. Epstein Cardiovascular risk factors impair native collateral development and may impair efficacy of therapeutic interventions Cardiovasc Res, May 1, 2008; 78(2): 257 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Rafii, B. Psaila, J. Butler, D. K. Jin, and D. Lyden Regulation of Vasculogenesis by Platelet-Mediated Recruitment of Bone Marrow-Derived Cells Arterioscler Thromb Vasc Biol, February 1, 2008; 28(2): 217 - 222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Dulak, J. Deshane, A. Jozkowicz, and A. Agarwal Heme Oxygenase-1 and Carbon Monoxide in Vascular Pathobiology: Focus on Angiogenesis Circulation, January 15, 2008; 117(2): 231 - 241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Pi and C. Patterson Twin Layers of Lightning: A New Role for the Chaperone Hsp90 in Angiogenesis Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 6 - 7. [Full Text] [PDF]
|
|
|
|
|
|
Z. Pasha, Y. Wang, R. Sheikh, D. Zhang, T. Zhao, and M. Ashraf Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium Cardiovasc Res, January 1, 2008; 77(1): 134 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Tongers and D. W. Losordo Frontiers in Nephrology: The Evolving Therapeutic Applications of Endothelial Progenitor Cells J. Am. Soc. Nephrol., November 1, 2007; 18(11): 2843 - 2852. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Xu, A. Mora, H. Shim, A. Stecenko, K. L. Brigham, and M. Rojas Role of the SDF-1/CXCR4 Axis in the Pathogenesis of Lung Injury and Fibrosis Am. J. Respir. Cell Mol. Biol., September 1, 2007; 37(3): 291 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Shmilovich, V. Deutsch, A. Roth, H. Miller, G. Keren, and J. George Circulating endothelial progenitor cells in patients with cardiac syndrome X Heart, September 1, 2007; 93(9): 1071 - 1076. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M Cubbon, A. Rajwani, and S. B Wheatcroft The impact of insulin resistance on endothelial function, progenitor cells and repair Diabetes and Vascular Disease Research, June 1, 2007; 4(2): 103 - 111. [Abstract] [PDF]
|
|
|
|
|
|
M. Kubo, T.-S. Li, R. Suzuki, M. Ohshima, S.-L. Qin, and K. Hamano Short-term pretreatment with low-dose hydrogen peroxide enhances the efficacy of bone marrow cells for therapeutic angiogenesis Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2582 - H2588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. L.T. Ballard and J. M. Edelberg Stem Cells and the Regeneration of the Aging Cardiovascular System Circ. Res., April 27, 2007; 100(8): 1116 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Heeschen, E. Chang, A. Aicher, and J. P. Cooke Endothelial Progenitor Cells Participate in Nicotine-Mediated Angiogenesis J. Am. Coll. Cardiol., November 28, 2006; (2006) j.jacc.2006.07.066v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Fujii, S.-H. Li, P. E. Szmitko, P. W.M. Fedak, and S. Verma C-Reactive Protein Alters Antioxidant Defenses and Promotes Apoptosis in Endothelial Progenitor Cells Arterioscler Thromb Vasc Biol, November 1, 2006; 26(11): 2476 - 2482. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Capoccia, R. M. Shepherd, and D. C. Link G-CSF and AMD3100 mobilize monocytes into the blood that stimulate angiogenesis in vivo through a paracrine mechanism Blood, October 1, 2006; 108(7): 2438 - 2445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ishikawa, M. Eguchi, M. Wada, Y. Iwami, K. Tono, H. Iwaguro, H. Masuda, T. Tamaki, and T. Asahara Establishment of a Functionally Active Collagen-Binding Vascular Endothelial Growth Factor Fusion Protein In Situ Arterioscler Thromb Vasc Biol, September 1, 2006; 26(9): 1998 - 2004. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-P. Lee, S.-W. Youn, H.-J. Cho, L. Li, T.-Y. Kim, H.-S. Yook, J.-W. Chung, J. Hur, C.-H. Yoon, K.-W. Park, et al. Integrin-Linked Kinase, a Hypoxia-Responsive Molecule, Controls Postnatal Vasculogenesis by Recruitment of Endothelial Progenitor Cells to Ischemic Tissue Circulation, July 11, 2006; 114(2): 150 - 159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zentilin, S. Tafuro, S. Zacchigna, N. Arsic, L. Pattarini, M. Sinigaglia, and M. Giacca Bone marrow mononuclear cells are recruited to the sites of VEGF-induced neovascularization but are not incorporated into the newly formed vessels Blood, May 1, 2006; 107(9): 3546 - 3554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S Enomoto, M Yoshiyama, T Omura, R Matsumoto, T Kusuyama, D Nishiya, Y Izumi, K Akioka, H Iwao, K Takeuchi, et al. Microbubble destruction with ultrasound augments neovascularisation by bone marrow cell transplantation in rat hind limb ischaemia Heart, April 1, 2006; 92(4): 515 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E.J. Reinders, T. J. Rabelink, and D. M. Briscoe Angiogenesis and Endothelial Cell Repair in Renal Disease and Allograft Rejection J. Am. Soc. Nephrol., April 1, 2006; 17(4): 932 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rafii and D. Lyden Contribution of Hematopoietic and Vascular Progenitor Cells to the Neoangiogenic Niche Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 181 - 185. [Full Text] [PDF]
|
|
|
|
|
|
F. G.P. Welt and D. W. Losordo Cell Therapy for Acute Myocardial Infarction: Curb Your Enthusiasm? Circulation, March 14, 2006; 113(10): 1272 - 1274. [Full Text] [PDF]
|
|
|
|
 |
|
 A. N. Patel, L. Geffner, R. F. Vina, J. Saslavsky, H. C. Urschel Jr, R. Kormos, and F. Benetti Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: A prospective randomized study J. Thorac. Cardiovasc. Surg., December 1, 2005; 130(6): 1631 - 1638. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Landazuri and W. R. Taylor The stem cell shell game. Focus on "The postnatal rat aorta contains pericyte progenitor cells that form spheroidal colonies in suspension culture" Am J Physiol Cell Physiol, December 1, 2005; 289(6): C1361 - C1362. [Full Text] [PDF]
|
|
|
|
|
|
D. M. Smadja, I. Bieche, G. Uzan, H. Bompais, L. Muller, C. Boisson-Vidal, M. Vidaud, M. Aiach, and P. Gaussem PAR-1 Activation on Human Late Endothelial Progenitor Cells Enhances Angiogenesis In Vitro With Upregulation of the SDF-1/CXCR4 System Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2321 - 2327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Nishiyama, K. Takaji, K. Kataoka, Y. Kurihara, M. Yoshimura, A. Kato, H. Ogawa, and H. Kurihara Id1 Gene Transfer Confers Angiogenic Property on Fully Differentiated Endothelial Cells and Contributes to Therapeutic Angiogenesis Circulation, November 1, 2005; 112(18): 2840 - 2850. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Lenk, V. Adams, P. Lurz, S. Erbs, A. Linke, S. Gielen, A. Schmidt, D. Scheinert, G. Biamino, F. Emmrich, et al. Therapeutical potential of blood-derived progenitor cells in patients with peripheral arterial occlusive disease and critical limb ischaemia Eur. Heart J., September 2, 2005; 26(18): 1903 - 1909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, G. M. Riha, S. Yan, M. Li, H. Chai, H. Yang, Q. Yao, and C. Chen Shear Stress Induces Endothelial Differentiation From a Murine Embryonic Mesenchymal Progenitor Cell Line Arterioscler Thromb Vasc Biol, September 1, 2005; 25(9): 1817 - 1823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Siepe, C. Heilmann, P. von Samson, P. Menasche, and F. Beyersdorf Stem cell research and cell transplantation for myocardial regeneration Eur. J. Cardiothorac. Surg., August 1, 2005; 28(2): 318 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. J. Dzau, M. Gnecchi, A. S. Pachori, F. Morello, and L. G. Melo Therapeutic Potential of Endothelial Progenitor Cells in Cardiovascular Diseases Hypertension, July 1, 2005; 46(1): 7 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Cho, S.-W. Youn, S.-I. Cheon, T.-Y. Kim, J. Hur, S.-Y. Zhang, S. P. Lee, K.-W. Park, M.-M. Lee, Y.-S. Choi, et al. Regulation of Endothelial Cell and Endothelial Progenitor Cell Survival and Vasculogenesis by Integrin-Linked Kinase Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1154 - 1160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Costa and D. I. Simon Molecular Basis of Restenosis and Drug-Eluting Stents Circulation, May 3, 2005; 111(17): 2257 - 2273. [Full Text] [PDF]
|
|
|
|
|
|
P. L Weissberg and A. Qasim Stem cell therapy for myocardial repair Heart, May 1, 2005; 91(5): 696 - 702. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Murasawa and T. Asahara Endothelial Progenitor Cells for Vasculogenesis Physiology, February 1, 2005; 20(1): 36 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Goligorsky Whispers and shouts in the pathogenesis of acute renal ischaemia Nephrol. Dial. Transplant., February 1, 2005; 20(2): 261 - 266. [Full Text] [PDF]
|
|
|
|
|
|
O. M. Tepper, J. M. Capla, R. D. Galiano, D. J. Ceradini, M. J. Callaghan, M. E. Kleinman, and G. C. Gurtner Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells Blood, February 1, 2005; 105(3): 1068 - 1077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Iwase, N. Nagaya, T. Fujii, T. Itoh, H. Ishibashi-Ueda, M. Yamagishi, K. Miyatake, T. Matsumoto, S. Kitamura, and K. Kangawa Adrenomedullin Enhances Angiogenic Potency of Bone Marrow Transplantation in a Rat Model of Hindlimb Ischemia Circulation, January 25, 2005; 111(3): 356 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Grisar, D. Aletaha, C. W. Steiner, T. Kapral, S. Steiner, D. Seidinger, G. Weigel, I. Schwarzinger, W. Wolozcszuk, G. Steiner, et al. Depletion of Endothelial Progenitor Cells in the Peripheral Blood of Patients With Rheumatoid Arthritis Circulation, January 18, 2005; 111(2): 204 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Schuh, S. Breuer, R. Al Dashti, N. Sulemanjee, P. Hanrath, C. Weber, B. F. Uretsky, and E. R. Schwarz Administration of Vascular Endothelial Growth Factor Adjunctive to Fetal Cardiomyocyte Transplantation and Improvement of Cardiac Function in the Rat Model Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2005; 10(1): 55 - 66. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. Van Oosterom, and E. A. De Bruijn Vascular Endothelial Growth Factor and Angiogenesis Pharmacol. Rev., December 1, 2004; 56(4): 549 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Bieberich, J. Silva, G. Wang, K. Krishnamurthy, and B. G. Condie Selective apoptosis of pluripotent mouse and human stem cells by novel ceramide analogues prevents teratoma formation and enriches for neural precursors in ES cell-derived neural transplants J. Cell Biol., November 22, 2004; 167(4): 723 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Choi, J. Hur, C.-H. Yoon, J.-H. Kim, C.-S. Lee, S.-W. Youn, I.-Y. Oh, C. Skurk, T. Murohara, Y.-B. Park, et al. Augmentation of Therapeutic Angiogenesis Using Genetically Modified Human Endothelial Progenitor Cells with Altered Glycogen Synthase Kinase-3{beta} Activity J. Biol. Chem., November 19, 2004; 279(47): 49430 - 49438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Weber, A. Schober, and A. Zernecke Chemokines: Key Regulators of Mononuclear Cell Recruitment in Atherosclerotic Vascular Disease Arterioscler Thromb Vasc Biol, November 1, 2004; 24(11): 1997 - 2008. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kong, L. G. Melo, M. Gnecchi, L. Zhang, G. Mostoslavsky, C. C. Liew, R. E. Pratt, and V. J. Dzau Cytokine-Induced Mobilization of Circulating Endothelial Progenitor Cells Enhances Repair of Injured Arteries Circulation, October 5, 2004; 110(14): 2039 - 2046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Melo, M. Gnecchi, A. S. Pachori, D. Kong, K. Wang, X. Liu, R. E. Pratt, and V. J. Dzau Endothelium-Targeted Gene and Cell-Based Therapies for Cardiovascular Disease Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1761 - 1774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Asahara and A. Kawamoto Endothelial progenitor cells for postnatal vasculogenesis Am J Physiol Cell Physiol, September 1, 2004; 287(3): C572 - C579. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.G Melo, M Gnecchi, A.S Pachori, K Wang, and V.J Dzau Gene- and cell-based therapies for cardiovascular diseases: current status and future directions Eur. Heart J. Suppl., September 1, 2004; 6(suppl_E): E24 - E35. [Abstract] [Full Text]
|
|
|
|
|
|
T. Kinnaird, E. Stabile, M. S. Burnett, and S. E. Epstein Bone Marrow-Derived Cells for Enhancing Collateral Development: Mechanisms, Animal Data, and Initial Clinical Experiences Circ. Res., August 20, 2004; 95(4): 354 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Yamaoka-Tojo, M. Ushio-Fukai, L. Hilenski, S. I. Dikalov, Y. E. Chen, T. Tojo, T. Fukai, M. Fujimoto, N. A. Patrushev, N. Wang, et al. IQGAP1, a Novel Vascular Endothelial Growth Factor Receptor Binding Protein, Is Involved in Reactive Oxygen Species--Dependent Endothelial Migration and Proliferation Circ. Res., August 6, 2004; 95(3): 276 - 283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hattan, D. Warltier, W. Gu, C. Kolz, W. M. Chilian, and D. Weihrauch Autologous vascular smooth muscle cell-based myocardial gene therapy to induce coronary collateral growth Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H488 - H493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Gulati, D. Jevremovic, T. A. Witt, L. S. Kleppe, R. G. Vile, A. Lerman, and R. D. Simari Modulation of the vascular response to injury by autologous blood-derived outgrowth endothelial cells Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H512 - H517. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Losordo and S. Dimmeler Therapeutic Angiogenesis and Vasculogenesis for Ischemic Disease: Part II: Cell-Based Therapies Circulation, June 8, 2004; 109(22): 2692 - 2697. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Raymond, F. Guilbert, A. Metcalfe, G. Gevry, I. Salazkin, and O. Robledo Role of the Endothelial Lining in Recurrences After Coil Embolization: Prevention of Recanalization by Endothelial Denudation Stroke, June 1, 2004; 35(6): 1471 - 1475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-i. Hiasa, M. Ishibashi, K. Ohtani, S. Inoue, Q. Zhao, S. Kitamoto, M. Sata, T. Ichiki, A. Takeshita, and K. Egashira Gene Transfer of Stromal Cell-Derived Factor-1{alpha} Enhances Ischemic Vasculogenesis and Angiogenesis via Vascular Endothelial Growth Factor/Endothelial Nitric Oxide Synthase-Related Pathway: Next-Generation Chemokine Therapy for Therapeutic Neovascularization Circulation, May 25, 2004; 109(20): 2454 - 2461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. MELO, A. S. PACHORI, D. KONG, M. GNECCHI, K. WANG, R. E. PRATT, and V. J. DZAU Gene and cell-based therapies for heart disease FASEB J, April 1, 2004; 18(6): 648 - 663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rehman, D. Traktuev, J. Li, S. Merfeld-Clauss, C. J. Temm-Grove, J. E. Bovenkerk, C. L. Pell, B. H. Johnstone, R. V. Considine, and K. L. March Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells Circulation, March 16, 2004; 109(10): 1292 - 1298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Xaymardan, J. Zheng, I. Duignan, A. Chin, J. M. Holm, V. L.T. Ballard, and J. M. Edelberg Senescent Impairment in Synergistic Cytokine Pathways That Provide Rapid Cardioprotection in the Rat Heart J. Exp. Med., March 15, 2004; 199(6): 797 - 804. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ribourtout and J. Raymond Gene Therapy and Endovascular Treatment of Intracranial Aneurysms Stroke, March 1, 2004; 35(3): 786 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Downs, E. R. Hellman, J. McHugh, K. Barrickman, and K. E. Inman Investigation into a role for the primitive streak in development of the murine allantois Development, January 1, 2004; 131(1): 37 - 55. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Cho, H.-S. Kim, M.-M. Lee, D.-H. Kim, H.-J. Yang, J. Hur, K.-K. Hwang, S. Oh, Y.-J. Choi, I.-H. Chae, et al. Mobilized Endothelial Progenitor Cells by Granulocyte-Macrophage Colony-Stimulating Factor Accelerate Reendothelialization and Reduce Vascular Inflammation After Intravascular Radiation Circulation, December 9, 2003; 108(23): 2918 - 2925. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Herder, T. Tonn, R. Oostendorp, S. Becker, U. Keller, C. Peschel, M. Grez, and E. Seifried Sustained Expansion and Transgene Expression of Coagulation Factor VIII-Transduced Cord Blood-Derived Endothelial Progenitor Cells Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2266 - 2272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. E. Szmitko, C.-H. Wang, R. D. Weisel, G. A. Jeffries, T. J. Anderson, and S. Verma Biomarkers of Vascular Disease Linking Inflammation to Endothelial Activation: Part II Circulation, October 28, 2003; 108(17): 2041 - 2048. [Full Text] [PDF]
|
|
|
|
|
|
B. R. Stoll, C. Migliorini, A. Kadambi, L. L. Munn, and R. K. Jain A mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors: implications for antiangiogenic therapy Blood, October 1, 2003; 102(7): 2555 - 2561. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Forrester, M. J. Price, and R. R. Makkar Stem Cell Repair of Infarcted Myocardium: An Overview for Clinicians Circulation, September 2, 2003; 108(9): 1139 - 1145. [Full Text] [PDF]
|
|
|
|
|
|
C. Heeschen, A. Aicher, R. Lehmann, S. Fichtlscherer, M. Vasa, C. Urbich, C. Mildner-Rihm, H. Martin, A. M. Zeiher, and S. Dimmeler Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization Blood, August 15, 2003; 102(4): 1340 - 1346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T.-S. Li, K. Hamano, M. Nishida, M. Hayashi, H. Ito, A. Mikamo, and M. Matsuzaki CD117+ stem cells play a key role in therapeutic angiogenesis induced by bone marrow cell implantation Am J Physiol Heart Circ Physiol, August 7, 2003; 285(3): H931 - H937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hristov, W. Erl, and P. C. Weber Endothelial Progenitor Cells: Mobilization, Differentiation, and Homing Arterioscler Thromb Vasc Biol, July 1, 2003; 23(7): 1185 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
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C. Patterson The Ponzo Effect: Endothelial Progenitor Cells Appear on the Horizon Circulation, June 24, 2003; 107(24): 2995 - 2997. [Full Text] [PDF]
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P. E. Szmitko, P. W.M. Fedak, R. D. Weisel, D. J. Stewart, M. J.B. Kutryk, and S. Verma Endothelial Progenitor Cells: New Hope for a Broken Heart Circulation, June 24, 2003; 107(24): 3093 - 3100. [Full Text] [PDF]
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H. M. Nugent and E. R. Edelman Tissue Engineering Therapy for Cardiovascular Disease Circ. Res., May 30, 2003; 92(10): 1068 - 1078. [Abstract] [Full Text] [PDF]
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A. Luttun and P. Carmeliet De novo vasculogenesis in the heart Cardiovasc Res, May 1, 2003; 58(2): 378 - 389. [Abstract] [Full Text] [PDF]
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H. Masuda and T. Asahara Post-natal endothelial progenitor cells for neovascularization in tissue regeneration Cardiovasc Res, May 1, 2003; 58(2): 390 - 398. [Abstract] [Full Text] [PDF]
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T. Suzuki, M. Nishida, S. Futami, K. Fukino, T. Amaki, K. Aizawa, S. Chiba, H. Hirai, K. Maekawa, and R. Nagai Neoendothelialization after peripheral blood stem cell transplantation in humans: A case report of a Tokaimura nuclear accident victim Cardiovasc Res, May 1, 2003; 58(2): 487 - 492. [Abstract] [Full Text] [PDF]
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A. Aicher, W. Brenner, M. Zuhayra, C. Badorff, S. Massoudi, B. Assmus, T. Eckey, E. Henze, A. M. Zeiher, and S. Dimmeler Assessment of the Tissue Distribution of Transplanted Human Endothelial Progenitor Cells by Radioactive Labeling Circulation, April 29, 2003; 107(16): 2134 - 2139. [Abstract] [Full Text] [PDF]
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T. M. DOHERTY, P. K. SHAH, and T. B. RAJAVASHISTH Cellular origins of atherosclerosis: towards ontogenetic endgame? FASEB J, April 1, 2003; 17(6): 592 - 597. [Full Text] [PDF]
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J. Rehman, J. Li, C. M. Orschell, and K. L. March Peripheral Blood "Endothelial Progenitor Cells" Are Derived From Monocyte/Macrophages and Secrete Angiogenic Growth Factors Circulation, March 4, 2003; 107(8): 1164 - 1169. [Abstract] [Full Text] [PDF]
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E. C. Perin, Y.-J. Geng, and J. T. Willerson Adult Stem Cell Therapy in Perspective Circulation, February 25, 2003; 107(7): 935 - 938. [Full Text] [PDF]
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O. M. Tepper, R. D. Galiano, J. M. Capla, C. Kalka, P. J. Gagne, G. R. Jacobowitz, J. P. Levine, and G. C. Gurtner Human Endothelial Progenitor Cells From Type II Diabetics Exhibit Impaired Proliferation, Adhesion, and Incorporation Into Vascular Structures Circulation, November 26, 2002; 106(22): 2781 - 2786. [Abstract] [Full Text] [PDF]
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 Y. Yang, J.-Y. Min, J. S. Rana, Q. Ke, J. Cai, Y. Chen, J. P. Morgan, and Y.-F. Xiao VEGF enhances functional improvement of postinfarcted hearts by transplantation of ESC-differentiated cells J Appl Physiol, September 1, 2002; 93(3): 1140 - 1151. [Abstract] [Full Text] [PDF]
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S. Murasawa, J. Llevadot, M. Silver, J. M. Isner, D. W. Losordo, and T. Asahara Constitutive Human Telomerase Reverse Transcriptase Expression Enhances Regenerative Properties of Endothelial Progenitor Cells Circulation, August 27, 2002; 106(9): 1133 - 1139. [Abstract] [Full Text] [PDF]
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E. G. Nabel Stem Cells Combined With Gene Transfer for Therapeutic Vasculogenesis: Magic Bullets? Circulation, February 12, 2002; 105(6): 672 - 674. [Full Text] [PDF]
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