This Article Abstract Full Text (PDF) Methods Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kalka, C. Articles by Asahara, T. Search for Related Content PubMed PubMed Citation Articles by Kalka, C. Articles by Asahara, T. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Stem Cells Related Collections Angiogenesis Peripheral vascular disease Gene therapy

(Circulation Research. 2000;86:1198.)
© 2000 American Heart Association, Inc.

Clinical Research

Vascular Endothelial Growth Factor₁₆₅ Gene Transfer Augments Circulating Endothelial Progenitor Cells in Human Subjects

Christoph Kalka, Haruchika Masuda, Tomono Takahashi, Rebecca Gordon, Oren Tepper, Edwin Gravereaux, Ann Pieczek, Hideki Iwaguro, Shin-Ichiro Hayashi, Jeffrey M. Isner, Takayuki Asahara

From the Departments of Medicine (Cardiology) and Biomedical Research, St. Elizabeth’s Medical Center, Tufts School of Medicine, Boston, Mass.

Correspondence to Jeffrey M. Isner, MD, and T. Asahara, MD, PhD, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.edu

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Abstract—Preclinical studies in animal models and early results of clinical trials in patients suggest that intramuscular injection of naked plasmid DNA encoding vascular endothelial growth factor (VEGF) can promote neovascularization of ischemic tissues. Such neovascularization has been attributed exclusively to sprout formation of endothelial cells derived from preexisting vessels. We investigated the hypothesis that VEGF gene transfer may also augment the population of circulating endothelial progenitor cells (EPCs). In patients with critical limb ischemia receiving VEGF gene transfer, gene expression was documented by a transient increase in plasma levels of VEGF. A culture assay documented a significant increase in EPCs (219%, P<0.001), whereas patients who received an empty vector had no change in circulating EPCs, as was the case for volunteers who received saline injections (VEGF versus empty vector, P<0.001; VEGF versus saline, P<0.005). Fluorescence-activated cell sorter analysis disclosed an overall increase of up to 30-fold in endothelial lineage markers KDR (VEGF receptor-2), VE-cadherin, CD34, _vß₃, and E-selectin after VEGF gene transfer. Constitutive overexpression of VEGF in patients with limb ischemia augments the population of circulating EPCs. These findings support the notion that neovascularization of human ischemic tissues after angiogenic growth factor therapy is not limited to angiogenesis but involves circulating endothelial precursors that may home to ischemic foci and differentiate in situ through a process of vasculogenesis.

Key Words: vascular endothelial growth factor • gene therapy • endothelial progenitor cells

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Recent investigations have established the feasibility of using recombinant formulations or gene transfer of angiogenic growth factors to expedite and augment collateral artery development in patients with tissue ischemia.^{1 2 3 4} Such postnatal neovascularization was initially considered synonymous with proliferation and migration of preexisting, fully differentiated endothelial cells (ECs) resident within parent vessels, ie, angiogenesis.^{5 6} The demonstration, however, of postnatal circulating bone marrow–derived endothelial progenitor cells (EPCs) that may home to sites of neovascularization and differentiate into ECs in situ⁷ is consistent with "vasculogenesis,"⁶ a critical paradigm for establishment of the primordial vascular network in the embryo. Although the proportional contributions of angiogenesis and vasculogenesis to neovascularization of adult organisms remain to be clarified, the notion that growth and development of new blood vessels in the adult is not restricted to angiogenesis but encompasses both embryonic mechanisms has now been verified by several laboratories.^{8 9 10}

Among the mechanisms that may modulate the contribution of vasculogenesis to postnatal neovascularization, we considered that certain angiogenic growth factors, which are acknowledged to promote both angiogenesis and vasculogenesis in the embryo¹¹ but have been assumed to promote neovascularization exclusively by angiogenesis in the adult,^{12 13 14} may in fact promote migration, proliferation, and mobilization of EPCs from adult bone marrow. Indeed, investigations performed in our laboratory using a bone marrow transplant model established that vascular endothelial growth factor (VEGF) may mobilize EPCs from murine bone marrow, resulting in augmented neovascularization.¹⁵

Accordingly, the current study was designed to test the hypothesis that intramuscular gene transfer of naked plasmid DNA encoding human VEGF (phVEGF₁₆₅) may increase the number of circulating human EPCs in patients with critical limb ischemia.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion References

 
Study Subjects
The potential for VEGF to enhance the population of circulating EPCs was serially monitored in 20 patients (11 women and 9 men, age 59±16 years) undergoing intramuscular phVEGF₁₆₅ gene transfer for critical limb ischemia. The same studies were performed on 9 patients who did not receive phVEGF₁₆₅ gene therapy. Four of these were healthy volunteers (4 men) ranging in age from 30 to 43 years (36±3), who were injected with normal saline. The remaining 5 patients included 2 women and 3 men with critical limb ischemia ages 48 to 78 years (67±12), who had been randomly assigned to receive a control (empty) vector.

Intramuscular phVEGF₁₆₅ Transfer
The patients undergoing gene therapy received the eukaryotic expression vector pUC118 encoding VEGF₁₆₅ transcriptionally regulated by the cytomegalovirus promoter/enhancer. A total of 4000 µg of DNA in 8 aliquots of 2.5 mL of sterile saline was administered at different sites into the ischemic limb by direct intramuscular injection.

Plasma VEGF Levels
Plasma levels of VEGF were measured by an ELISA assay in patients before intramuscular injection and weekly up to 4 weeks after the initial set of injections.³

Isolation of Mononuclear Cells (MNCs)
Blood samples were obtained from all individuals before and, weekly, up to 4 weeks after intramuscular injections. Peripheral blood MNCs were isolated in a cell preparation tube by density gradient centrifugation.

EPC Culture Assay
The culture system used in our laboratory to quantify circulating EPCs has been described elsewhere.¹⁵ MNCs from 500 µL of peripheral blood were cultured in EC basal medium-2 supplemented with endothelial cell growth medium (EGM-2) microvascular (MV) Single Quots. After 4 days, fluorescence staining of adherent cells was used to detect the binding of Ulex europaeus agglutinin I (UEA-1) and the uptake of acetylated LDL (acLDL). Dual-staining cells positive for both FITC-labeled UEA-1 and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine (DiI)–labeled acLDL were judged as EPCs and counted per well.

Flow Cytometry Analysis
A total of 2 to 3x10⁵ cells were incubated for 30 minutes at 4°C with monoclonal antibodies prepared against KDR, VE-cadherin, CD62E (E-selectin), CD51/61 (_vß₃), CD31, CD34, and CD14. Quantitative fluorescence-activated cell sorter (FACS) analysis was performed on a FACStar flow cytometer.

Statistical Analysis
All results are expressed as mean±SEM. Statistical significance was evaluated using unpaired Student t test and ANOVA. A value of P<0.05 was interpreted to denote statistical significance. The relationship between variables was determined by linear regression analysis.

An expanded Materials and Methods section is available online at http://www.circresaha.org.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
To evaluate the effect of VEGF on EPC kinetics, we obtained 100 samples of peripheral blood from patients with critical limb ischemia undergoing VEGF₁₆₅ gene transfer. A total of 25 samples were obtained from patients in whom injection of empty DNA vector was performed. An additional 20 samples were obtained from healthy individuals who received saline injections.

Transgene Expression After VEGF Gene Therapy
Plasma levels of VEGF transiently increased in all patients after gene transfer. A mean 2.1±0.3-fold increase over baseline at day 7 (P<0.001) was followed by persistent elevation at day 14 (1.9±0.3-fold, P<0.001), day 21 (1.8±0.2-fold, P<0.01), and day 28 (1.5±0.2-fold, P<0.05, all versus baseline). The mean plasma VEGF concentrations increased from 33.1±5 pg/mL at baseline to a maximum value of 98.8±17 pg/mL after gene transfer (P<0.01). In contrast, no significant changes were documented in the control patients (Figure 1).

View larger version (32K): [in this window] [in a new window]   Figure 1. VEGF plasma levels and circulating EPCs of patients before and after intramuscular administration of phVEGF165 or empty vector. Concomitant with a significant rise in the VEGF plasma levels as determined by ELISA, the number of EPCs determined by the culture assay in the phVEGF165-treated group increased as early as treatment day 7 through posttreatment day 28. In contrast, no change in VEGF plasma levels or EPCs was observed in the control group. *P<0.01, **P<0.001, and ***P<0.0005 for increase of EPCs over baseline; #P<0.05, ##P<0.01, and ###P<0.001 for increase of VEGF plasma over baseline.

EPC Culture Assay After phVEGF₁₆₅ Gene Therapy
Two independent criteria were used to assess the effect of phVEGF₁₆₅ gene transfer on EPC kinetics. First, we applied a previously described¹⁵ culture assay in which EPCs were quantified by identification of cultured cells demonstrating both UEA-1 reactivity and uptake of acLDL (Figure 2). The impact of VEGF on circulating EPCs could be detected by culture assay from day 7 (80% increase versus baseline, P<0.0005) through day 14 (154% increase versus baseline, P<0.0005), day 21 (82% increase versus baseline, P<0.05), and day 28 after treatment (153% increase versus baseline, P<0.005). The increase in EPCs correlated with the rise in VEGF plasma levels (R²=0.83; P<0.0001) (Figure 1B online; available at http://www.circresaha.org). Patients injected with empty vector had comparable numbers of EPCs at baseline but failed to exhibit a significant change in cultured EPCs. The number of cultured EPCs was significantly different between the VEGF-treated patients and the control vector–injected group as early as day 7 (P<0.001) and over the following 3 weeks (day 14, P<0.005; day 21, P<0.05; day 28, P<0.005). Likewise, the saline-injected group showed no significant change in EPC counts over 4 weeks after gene transfer. There was no significant difference in EPC count between the saline- and empty vector–treated groups (Figure 1).

View larger version (19K): [in this window] [in a new window]   Figure 2. Representative fluorescence photomicrographs of EPCs cultured 4 days after isolation from peripheral blood. A, Cultured EPCs, identified by positive double staining of FITC-conjugated UEA-1 and of DiI-labeled acetylated LDL, from a representative control patient after intramuscular injection of an empty vector. B, Identical magnification of EPCs from a representative patient who received intramuscular gene transfer of naked DNA encoding for VEGF165.

FACS Analysis
FACS analysis was used as a second independent measure to quantify the population of EPCs mobilized in response to VEGF gene transfer. Overall, we observed an average increase in the expression levels of the EC-specific antigens KDR (22.1±1.5-fold versus baseline, P<0.005), VE-cadherin (26±2-fold versus baseline, P<0.001), and CD34 (8±1.5-fold versus baseline, P<0.01). The number of KDR- and VE-cadherin–positive cells increased significantly over baseline values (KDR, 5.6±0.8x10³/mL; VE-cadherin, 4.5±1.2x10³/mL) as early as day 7 (KDR, 131.2±36 10³/mL [P<0.005]; VE-cadherin, 134±45x10³/mL [P<0.01]) and continued to be elevated over the entire observation period (day 14, KDR, 112±35 10³/mL [P<0.01], and VE-cadherin, 103±19x10³/mL [P<0.0005]; day 21, KDR, 106.4±32 10³/mL [P<0.01], and VE-cadherin, 105±26x10³/mL [P<0.005]; day 28, KDR, 148.9±48 10³/mL [P<0.05], and VE-cadherin, 132.6±38x10³/mL, [P<0.02]) (Figure 3). In contrast, no significant changes were observed in the group injected with empty plasmid or in the group of healthy volunteers injected with saline. Likewise, the number of CD14-positive cells remained unchanged in all 3 study groups (data not shown). Representative of the measurements taken at the aforementioned time points, Figure 4 shows the expression values at day 14. The increase over baseline in VEGF plasma levels and in VE-cadherin–positive cells showed a high correlation at this time point (R²=0.82; P<0.0001) (Figure 1C online; available at http://www.circresaha.org). Findings in the VEGF-treated group differed significantly from both control groups.

View larger version (22K): [in this window] [in a new window]   Figure 3. Quantitative evaluation of circulating EPCs by FACS analysis. MNCs were analyzed for expression of the EC-specific antigens VE-cadherin (A) and KDR (B) at baseline and over a time interval of 4 weeks after treatment. After intramuscular phVEGF165 gene transfer, the number of VE-cadherin– and KDR-positive MNCs increased significantly and remained elevated over the entire observation period; in contrast, no changes were observed in subjects receiving empty vector or saline injections.

View larger version (21K): [in this window] [in a new window]   Figure 4. Representative expression pattern of EC-specific antigens on peripheral blood MNCs. Number of MNCs expressing EC-specific antigens in patients treated with phVEGF165, empty vector, and saline are shown at baseline (before) and 14 days after treatment. A significant increase over baseline was observed for all investigated antigens after intramuscular VEGF gene transfer. In contrast, no change in expression for this panel of antigens was observed in patients receiving empty vector or saline.

To determine the relationship between the culture assay and the FACS analysis, we compared the individual increases in both assays at a representative time point (day 14), using the rise in the EPC count and in the number of VE-cadherin positive cells. The results revealed a positive correlation (R²=0.77; P<0.0005) (Figure 1A online; available at http://www.circresaha.org).

Expression of EC Adhesion Molecules
We also examined the effect of VEGF gene transfer on the expression of EC adhesion molecules. In patients subjected to VEGF gene transfer, the number of circulating MNCs with the surface expression of _vß₃ (CD51/61) and E-selectin (CD62E) increased during the observation period on average by 5±1-fold and 25±1-fold, respectively. In contrast, expression values in individuals receiving empty vector and saline treatment remained unchanged. The expression pattern and levels of E-selectin were very similar to those of VE-cadherin and KDR, with maximal values at day 7 and day 28 after the treatment, whereas the levels for _vß₃ were slightly different with a maximal expression at day 14. At the representative time point, day 14, levels of _vß₃ and E-selectin expression in the VEGF-treated group increased significantly compared with baseline (for _vß₃ [CD51/61], 16.7±6 versus 1.9±0.7x10³/mL [P<0.05], and for E-selectin [CD62E], 101±37 versus 3.6±1x10³/mL [P<0.02]) and compared with both control groups (for _vß₃ [CD51/61], VEGF versus empty plasmid, P<0.05, and VEGF versus saline, P<0.05; for E-selectin [CD62E], VEGF versus empty plasmid, P<0.02, and VEGF versus saline, P<0.02) (Figure 4).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Preclinical studies in animal models¹⁶ and early studies performed in small numbers of patients with lower limb¹⁷ and myocardial^{2 4} ischemia support the notion that gene transfer of VEGF DNA may promote neovascularization of ischemic tissues. These previous reports established that direct injection of phVEGF₁₆₅ into muscle of the ischemic limb,^{3 17} as well as into ischemic myocardium,² transiently elevates plasma VEGF levels in the systemic circulation, a finding that is confirmed in the patients described above.

The current series of patients further establishes that the rise in plasma levels of VEGF is associated with modulation of EPC kinetics after VEGF gene transfer. The increase in EPCs was statistically significant as early as 1 week after gene transfer and remained statistically significant at 2, 3, and 4 weeks follow-up. By comparison, EPC kinetics in the control subjects—including patients with or without critical limb ischemia, injected with empty vector or saline—were unchanged.

Because of limitations in the types of analyses that may be performed in human subjects, the origin and fate of the augmented population of circulating EPCs in these patients must be inferred from experiments performed previously in live animal models. Daily intraperitoneal injection of recombinant human VEGF₁₆₅ (rhVEGF) to C57BL/6J mice for 1 week increased the total number of circulating EPCs.¹⁵ These effects were abrogated by coincidental application of a neutralizing antibody prepared against rhVEGF.

When mice were pretreated with rhVEGF or control buffer for 7 days before cornea micropocket injury and then examined on day 7 after injury (ie, 7 days after the last dose of rhVEGF), in situ BS-1 lectin staining disclosed enhanced corneal neovascularization in the rhVEGF group compared with controls. These findings were reproduced in mice receiving bone marrow transplanted from transgenic mice constitutively expressing ß-galactosidase encoded by lacZ under the transcriptional regulation of an EC-specific gene, tie-2, to establish direct evidence for incorporation of bone marrow–derived EPCs into capillaries and stromal tissue of the corneal neovasculature.

Like fully differentiated ECs,¹⁸ EPCs express specific endothelial antigens, including KDR (VEGF receptor-2), CD34, and VE-cadherin.^{8 9 19} Although KDR and VE-cadherin are generally considered to distinguish EPCs from hematopoietic stem cells,^{20 21} there exists no epitope of which the expression is restricted exclusively to EPCs versus fully differentiated ECs. There is, however, evidence that EPCs constitute the preponderance of such circulating, bone marrow–derived endothelial lineage cells. First, the present work indicates that the population of circulating EPCs in normal individuals (3 to 5x10³/mL) far exceeds the number of differentiated ECs circulating in peripheral blood (2 to 3/mL).²² Second, animal experiments from our own laboratory have suggested that the majority of the cellular population mobilized into the circulation and then incorporated into neovascular foci after VEGF administration is most consistent with bone marrow–derived EPCs.¹⁵

These clinical findings call into question certain fundamental concepts regarding the mechanisms by which VEGF promotes blood vessel growth and development in adult organisms. The role of VEGF in postnatal neovascularization has been previously considered synonymous with proliferation and migration of preexisting, fully differentiated ECs resident within parent vessels, ie, sprout formation or angiogenesis.^{6 12 18} The finding that VEGF augments the number of circulating EPCs in human patients, together with the aforementioned murine experiments,¹⁵ implies that its impact on postnatal neovascularization is the combined result of vasculogenesis as well as angiogenesis. The proportional contributions of angiogenesis and vasculogenesis to postnatal neovascularization, including the extent to which each is influenced by VEGF, remain to be clarified.

Finally, these findings have implications for the use of naked DNA in human gene therapy. Earlier studies suggested that the low transfection efficiency associated with the use of naked DNA might make it unsuitable for therapeutic applications in trials of human gene therapy. Subsequent experience in live animal models, however, demonstrated that transfer of genes encoding for secreted proteins, such as VEGF, could yield important biological effects due to the paracrine effects of the secreted gene product.²³ The current demonstration that VEGF gene therapy augments the compartment of circulating EPCs constitutes further evidence that gene transfer of naked DNA may indeed be sufficient to modulate the biology of human subjects.

	Acknowledgments

 
This work was supported in part by NIH Grants HL53354, HL57516, and HL60911 (to J.M.I.) and by a grant from Cologne Fortune Program, Cologne, Germany (to C.K.).

Received January 14, 2000; accepted May 4, 2000.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 
1. Schumacher B, Pecher P, vonSpecht BU, Stegmann T. Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation. 1998;97:645–650.[Abstract/Free Full Text]

2. Losordo DW, Vale PR, Symes J, Dunnington C, Esakof D, Maysky M, Ashare A, Lathi K, Isner JM. 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.[Abstract/Free Full Text]

3. Baumgartner I, Pieczek A, Manor O, Blair R, Kearney M, Walsh K, Isner JM. Constitutive expression of phVEGF₁₆₅ after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation. 1998;97:1114–1123.[Abstract/Free Full Text]

4. Rosengart TK, Lee LY, Patel SR, Sanborn TA, Parikh M, Bergman GW, Hachamovitch R, Szulc M, Kligfield PD, Okin PM, Hahn RT, Devereaux RB, Post MR, Hackett NR, Foster T, Grasso TM, Lesser ML, Isom W, Crystal RG. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF₁₂₁ cDNA to individuals with clinically significant severe coronary artery disease. Circulation. 1999;100:468–474.[Abstract/Free Full Text]

5. Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267:10931–10934.[Free Full Text]

6. Risau W. Mechanisms of angiogenesis. Nature. 1997;386:671–674.[Medline] [Order article via Infotrieve]

7. Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearney M, Magner M, Isner JM. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999;85:221–228.[Abstract/Free Full Text]

8. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:965–967.

9. Shi Q, Rafii S, Wu MH-D, Wijelath ES, Yu C, Ishida A, Fujita Y, Kothari S, Mohle R, Sauvage LR, Moore MAS, Storb RF, Hammond WP. Evidence for circulating bone marrow-derived endothelial cells. Blood. 1998;92:362–367.[Abstract/Free Full Text]

10. Lin Y, Weisdorf DJ, Solovey A, Hebbel RP. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest. 2000;105:71–77.[Medline] [Order article via Infotrieve]

11. Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NPH, Risau W, Ulrich A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993;72:835–846.[Medline] [Order article via Infotrieve]

12. D’Amore PA, Thompson RW. Mechanisms of angiogenesis. Annu Rev Physiol. 1987;49:453–464.[Medline] [Order article via Infotrieve]

13. Klagsbrun M, D’Amore PA. Regulators of angiogenesis. Annu Rev Physiol. 1991;53:217–239.[Medline] [Order article via Infotrieve]

14. Brown LF, Detmar M, Claffey K, Nagy JA, Feng D, Dvorak AM, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine. In: Goldberg RE, ed. Regulation of Angiogenesis. Basel, Switzerland: Birkhäuser Verlag; 1997:233–269.

15. Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, Inai Y, Silver M, Isner JM. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J. 1999;18:3964–3972.[Medline] [Order article via Infotrieve]

16. Takeshita S, Tsurumi Y, Couffinhal T, Asahara T, Bauters C, Symes JF, Ferrara N, Isner JM. Gene transfer of naked DNA encoding for three isoforms of vascular endothelial growth factor stimulates collateral development in vivo. Lab Invest. 1996;75:487–502.[Medline] [Order article via Infotrieve]

17. Isner JM, Baumgartner I, Rauh G, Schainfeld R, Blair R, Manor O, Razvi S, Symes JF. Treatment of thromboangiitis obliterans (Buerger’s disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results. J Vasc Surg. 1998;28:964–975.[Medline] [Order article via Infotrieve]

18. Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 1998;91:3527.[Free Full Text]

19. Hatzopoulos AK, Folkman J, Vasile E, Eiselen GK, Rosenberg RD. Isolation and characterization of endothelial progenitor cells from mouse embryos. Development. 1998;125:1457–1468.[Abstract]

20. Nishikawa S, Hirashima M, Matsuyoshi N, Kodama H. Progressive lineage analysis by cell sorting and culture identifies Flk1⁺VE-cadherin⁺ cells at a diverging point of endothelial and hematopoietic lineages. Development. 1998;125:1747–1757.[Abstract]

21. Yamaguchi TP, Dumont DJ, Conlon RA, Breitman ML, Rossant J. flk-1, an flt-related receptor tyrosine kinase is an early marker for endothelial cell precursors. Development. 1993;118:489–498.[Abstract]

22. Solovey A, Lin Y, Brown P, Choong S, Wayner E, Hebbel RP. Circulating activated endothelial cells in sickle cell anemia. N Engl J Med. 1997;337:1582–1590.

23. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–1309.[Abstract/Free Full Text]

This article has been cited by other articles:

				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]

				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]

				A. Shabbir, D. Zisa, G. Suzuki, and T. Lee Heart failure therapy mediated by the trophic activities of bone marrow mesenchymal stem cells: a noninvasive therapeutic regimen Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1888 - H1897. [Abstract] [Full Text] [PDF]

				A.O. Robb, N.L. Mills, I.B.J. Smith, A. Short, O. Tura-Ceide, G.R. Barclay, A. Blomberg, H.O.D. Critchley, D.E. Newby, and F.C. Denison Influence of menstrual cycle on circulating endothelial progenitor cells Hum. Reprod., March 1, 2009; 24(3): 619 - 625. [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]

				S. Brunner, G.-H. Schernthaner, M. Satler, M. Elhenicky, F. Hoellerl, K. E. Schmid-Kubista, F. Zeiler, S. Binder, and G. Schernthaner Correlation of Different Circulating Endothelial Progenitor Cells to Stages of Diabetic Retinopathy: First In Vivo Data Invest. Ophthalmol. Vis. Sci., January 1, 2009; 50(1): 392 - 398. [Abstract] [Full Text] [PDF]

				R. P.W. Rouhl, R. J. van Oostenbrugge, J. Damoiseaux, J.-W. C. Tervaert, and J. Lodder Endothelial Progenitor Cell Research in Stroke: A Potential Shift in Pathophysiological and Therapeutical Concepts Stroke, July 1, 2008; 39(7): 2158 - 2165. [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]

				R. Ray, C. M. Herring, T. A. Markel, P. R. Crisostomo, M. Wang, B. Weil, T. Lahm, and D. R. Meldrum Deleterious effects of endogenous and exogenous testosterone on mesenchymal stem cell VEGF production Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2008; 294(5): R1498 - R1503. [Abstract] [Full Text] [PDF]

				A. Whittaker, J. S. Moore, M. Vasa-Nicotera, S. Stevens, and N. J. Samani Evidence for genetic regulation of endothelial progenitor cells and their role as biological markers of atherosclerotic susceptibility Eur. Heart J., February 1, 2008; 29(3): 332 - 338. [Abstract] [Full Text] [PDF]

				H.-J. Cho, N. Lee, J. Y. Lee, Y. J. Choi, M. Ii, A. Wecker, J.-O. Jeong, C. Curry, G. Qin, and Y.-s. Yoon Role of host tissues for sustained humoral effects after endothelial progenitor cell transplantation into the ischemic heart J. Exp. Med., December 24, 2007; 204(13): 3257 - 3269. [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]

				T. Okazaki, S. Ebihara, M. Asada, S. Yamanda, Y. Saijo, Y. Shiraishi, T. Ebihara, K. Niu, H. Mei, H. Arai, et al. Macrophage Colony-Stimulating Factor Improves Cardiac Function after Ischemic Injury by Inducing Vascular Endothelial Growth Factor Production and Survival of Cardiomyocytes Am. J. Pathol., October 1, 2007; 171(4): 1093 - 1103. [Abstract] [Full Text] [PDF]

				V. Rosti, M. Massa, R. Campanelli, M. De Amici, G. Piccolo, and V. Perfetti Vascular endothelial growth factor promoted endothelial progenitor cell mobilization into the peripheral blood of a patient with POEMS syndrome Haematologica, September 1, 2007; 92(9): 1291 - 1292. [Abstract] [Full Text] [PDF]

				Q. Zhao, Z. Liu, Z. Wang, C. Yang, J. Liu, and J. Lu Effect of Prepro-Calcitonin Gene-Related Peptide Expressing Endothelial Progenitor Cells on Pulmonary Hypertension Ann. Thorac. Surg., August 1, 2007; 84(2): 544 - 552. [Abstract] [Full Text] [PDF]

				A. Schmidt, K. Brixius, and W. Bloch Endothelial Precursor Cell Migration During Vasculogenesis Circ. Res., July 20, 2007; 101(2): 125 - 136. [Abstract] [Full Text] [PDF]

				E. Rullman, H. Rundqvist, D. Wagsater, H. Fischer, P. Eriksson, C. J. Sundberg, E. Jansson, and T. Gustafsson A single bout of exercise activates matrix metalloproteinase in human skeletal muscle J Appl Physiol, June 1, 2007; 102(6): 2346 - 2351. [Abstract] [Full Text] [PDF]

				K. Asosingh, S. Swaidani, M. Aronica, and S. C. Erzurum Th1- and Th2-Dependent Endothelial Progenitor Cell Recruitment and Angiogenic Switch in Asthma J. Immunol., May 15, 2007; 178(10): 6482 - 6494. [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]

				X.-X. Wang, F.-R. Zhang, Y.-P. Shang, J.-H. Zhu, X.-D. Xie, Q.-M. Tao, J.-H. Zhu, and J.-Z. Chen Transplantation of Autologous Endothelial Progenitor Cells May Be Beneficial in Patients With Idiopathic Pulmonary Arterial Hypertension: A Pilot Randomized Controlled Trial J. Am. Coll. Cardiol., April 10, 2007; 49(14): 1566 - 1571. [Abstract] [Full Text] [PDF]

				E. Shantsila, T. Watson, and G. Y.H. Lip Endothelial Progenitor Cells in Cardiovascular Disorders J. Am. Coll. Cardiol., February 20, 2007; 49(7): 741 - 752. [Abstract] [Full Text] [PDF]

				D. A. Goukassian, G. Qin, C. Dolan, T. Murayama, M. Silver, C. Curry, E. Eaton, C. Luedemann, H. Ma, T. Asahara, et al. Tumor Necrosis Factor-{alpha} Receptor p75 Is Required in Ischemia-Induced Neovascularization Circulation, February 13, 2007; 115(6): 752 - 762. [Abstract] [Full Text] [PDF]

				A. O Robb, N. L Mills, D. E Newby, and F. C Denison Endothelial progenitor cells in pregnancy Reproduction, January 1, 2007; 133(1): 1 - 9. [Abstract] [Full Text] [PDF]

				G. C. Schatteman, M. Dunnwald, and C. Jiao Biology of bone marrow-derived endothelial cell precursors Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H1 - H18. [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., December 19, 2006; 48(12): 2553 - 2560. [Abstract] [Full Text] [PDF]

				J Heidemann, D G Binion, W Domschke, and T Kucharzik Antiangiogenic therapy in human gastrointestinal malignancies. Gut, October 1, 2006; 55(10): 1497 - 1511. [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]

				N. Mehra, M. Penning, J. Maas, L. V. Beerepoot, N. van Daal, C. H. van Gils, R. H. Giles, and E. E. Voest Progenitor Marker CD133 mRNA Is Elevated in Peripheral Blood of Cancer Patients with Bone Metastases. Clin. Cancer Res., August 15, 2006; 12(16): 4859 - 4866. [Abstract] [Full Text] [PDF]

				A Allende, M C Madigan, and J M Provis Endothelial cell proliferation in the choriocapillaris during human retinal differentiation Br J Ophthalmol, August 1, 2006; 90(8): 1046 - 1051. [Abstract] [Full Text] [PDF]

				B. Li, E. E. Sharpe, A. B. Maupin, A. A. Teleron, A. L. Pyle, P. Carmeliet, and P. P. Young VEGF and PlGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularization FASEB J, July 1, 2006; 20(9): 1495 - 1497. [Abstract] [Full Text] [PDF]

				H.C. de Boer, C. Verseyden, L.H. Ulfman, J.J. Zwaginga, I. Bot, E.A. Biessen, T.J. Rabelink, and A.J. van Zonneveld Fibrin and Activated Platelets Cooperatively Guide Stem Cells to a Vascular Injury and Promote Differentiation Towards an Endothelial Cell Phenotype Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1653 - 1659. [Abstract] [Full Text] [PDF]

				N. Urao, M. Okigaki, H. Yamada, Y. Aadachi, K. Matsuno, A. Matsui, S. Matsunaga, K. Tateishi, T. Nomura, T. Takahashi, et al. Erythropoietin-Mobilized Endothelial Progenitors Enhance Reendothelialization via Akt-Endothelial Nitric Oxide Synthase Activation and Prevent Neointimal Hyperplasia Circ. Res., June 9, 2006; 98(11): 1405 - 1413. [Abstract] [Full Text] [PDF]

				T. Mohri, Y. Fujio, M. Maeda, T. Ito, T. Iwakura, Y. Oshima, Y. Uozumi, M. Segawa, H. Yamamoto, T. Kishimoto, et al. Leukemia Inhibitory Factor Induces Endothelial Differentiation in Cardiac Stem Cells J. Biol. Chem., March 10, 2006; 281(10): 6442 - 6447. [Abstract] [Full Text] [PDF]

				T. Okazaki, S. Ebihara, M. Asada, A. Kanda, H. Sasaki, and M. Yamaya Granulocyte colony-stimulating factor promotes tumor angiogenesis via increasing circulating endothelial progenitor cells and Gr1+CD11b+ cells in cancer animal models Int. Immunol., January 1, 2006; 18(1): 1 - 9. [Abstract] [Full Text] [PDF]

				E. L. Burnham, W. R. Taylor, A. A. Quyyumi, M. Rojas, K. L. Brigham, and M. Moss Increased Circulating Endothelial Progenitor Cells Are Associated with Survival in Acute Lung Injury Am. J. Respir. Crit. Care Med., October 1, 2005; 172(7): 854 - 860. [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]

				M. Sandri, V. Adams, S. Gielen, A. Linke, K. Lenk, N. Krankel, D. Lenz, S. Erbs, D. Scheinert, F. W. Mohr, et al. Effects of Exercise and Ischemia on Mobilization and Functional Activation of Blood-Derived Progenitor Cells in Patients With Ischemic Syndromes: Results of 3 Randomized Studies Circulation, June 28, 2005; 111(25): 3391 - 3399. [Abstract] [Full Text] [PDF]

				T. Okazaki, S. Ebihara, H. Takahashi, M. Asada, A. Kanda, and H. Sasaki Macrophage Colony-Stimulating Factor Induces Vascular Endothelial Growth Factor Production in Skeletal Muscle and Promotes Tumor Angiogenesis J. Immunol., June 15, 2005; 174(12): 7531 - 7538. [Abstract] [Full Text] [PDF]

				R. S. Herbst, A. Onn, and A. Sandler Angiogenesis and Lung Cancer: Prognostic and Therapeutic Implications J. Clin. Oncol., May 10, 2005; 23(14): 3243 - 3256. [Abstract] [Full Text] [PDF]

				C M Doerschuk Circulating endothelial progenitor cells in pulmonary inflammation Thorax, May 1, 2005; 60(5): 362 - 364. [Full Text] [PDF]

				P. Beaudry, J. Force, G. N. Naumov, A. Wang, C. H. Baker, A. Ryan, S. Soker, B. E. Johnson, J. Folkman, and J. V. Heymach Differential Effects of Vascular Endothelial Growth Factor Receptor-2 Inhibitor ZD6474 on Circulating Endothelial Progenitors and Mature Circulating Endothelial Cells: Implications for Use as a Surrogate Marker of Antiangiogenic Activity Clin. Cancer Res., May 1, 2005; 11(9): 3514 - 3522. [Abstract] [Full Text] [PDF]

				Y.-s. Yoon, S. Uchida, O. Masuo, M. Cejna, J.-S. Park, H.-c. Gwon, R. Kirchmair, F. Bahlman, D. Walter, C. Curry, et al. Progressive Attenuation of Myocardial Vascular Endothelial Growth Factor Expression Is a Seminal Event in Diabetic Cardiomyopathy: Restoration of Microvascular Homeostasis and Recovery of Cardiac Function in Diabetic Cardiomyopathy After Replenishment of Local Vascular Endothelial Growth Factor Circulation, April 26, 2005; 111(16): 2073 - 2085. [Abstract] [Full Text] [PDF]

				H. T. Hua, H. Albadawi, F. Entabi, M. Conrad, M. C. Stoner, B. T. Meriam, R. Sroufe, S. Houser, G. M. LaMuraglia, and M. T. Watkins Polyadenosine Diphosphate-Ribose Polymerase Inhibition Modulates Skeletal Muscle Injury Following Ischemia Reperfusion Arch Surg, April 1, 2005; 140(4): 344 - 351. [Abstract] [Full Text] [PDF]

				A. Aicher, A. M. Zeiher, and S. Dimmeler Mobilizing Endothelial Progenitor Cells Hypertension, March 1, 2005; 45(3): 321 - 325. [Abstract] [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]

				D. Scholz and W. Schaper Preconditioning of arteriogenesis Cardiovasc Res, February 1, 2005; 65(2): 513 - 523. [Abstract] [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]

				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]

				A. Shimizu, Y. Masuda, T. Mori, H. Kitamura, M. Ishizaki, Y. Sugisaki, and Y. Fukuda Vascular Endothelial Growth Factor165 Resolves Glomerular Inflammation and Accelerates Glomerular Capillary Repair in Rat Anti-Glomerular Basement Membrane Glomerulonephritis J. Am. Soc. Nephrol., October 1, 2004; 15(10): 2655 - 2665. [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]

				A. Kawamoto, T. Murayama, K. Kusano, M. Ii, T. Tkebuchava, S. Shintani, A. Iwakura, I. Johnson, P. von Samson, A. Hanley, et al. Synergistic Effect of Bone Marrow Mobilization and Vascular Endothelial Growth Factor-2 Gene Therapy in Myocardial Ischemia Circulation, September 14, 2004; 110(11): 1398 - 1405. [Abstract] [Full Text] [PDF]

				C. Urbich and S. Dimmeler Endothelial Progenitor Cells: Characterization and Role in Vascular Biology Circ. Res., August 20, 2004; 95(4): 343 - 353. [Abstract] [Full Text] [PDF]

				V. van Weel, M. M.L. Deckers, J. M. Grimbergen, K. J.M. van Leuven, J. H.P. Lardenoye, R. O. Schlingemann, G. P. van Nieuw Amerongen, J. H. van Bockel, V. W.M. van Hinsbergh, and P. H.A. Quax Vascular Endothelial Growth Factor Overexpression in Ischemic Skeletal Muscle Enhances Myoglobin Expression In Vivo Circ. Res., July 9, 2004; 95(1): 58 - 66. [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]

				C. Theopold, F. Yao, and E. Eriksson Gene Therapy in the Treatment of Lower Extremity Wounds International Journal of Lower Extremity Wounds, June 1, 2004; 3(2): 69 - 79. [Abstract] [PDF]

				T. J. Rabelink, H. C. de Boer, E. J.P. de Koning, and A.-J. van Zonneveld Endothelial Progenitor Cells: More Than an Inflammatory Response? Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 834 - 838. [Abstract] [Full Text]

				D. Kong, L. G. Melo, A. A. Mangi, L. Zhang, M. Lopez-Ilasaca, M. A. Perrella, C. C. Liew, R. E. Pratt, and V. J. Dzau Enhanced Inhibition of Neointimal Hyperplasia by Genetically Engineered Endothelial Progenitor Cells Circulation, April 13, 2004; 109(14): 1769 - 1775. [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]

				V. Adams, K. Lenk, A. Linke, D. Lenz, S. Erbs, M. Sandri, A. Tarnok, S. Gielen, F. Emmrich, G. Schuler, et al. Increase of Circulating Endothelial Progenitor Cells in Patients with Coronary Artery Disease After Exercise-Induced Ischemia Arterioscler Thromb Vasc Biol, April 1, 2004; 24(4): 684 - 690. [Abstract] [Full Text] [PDF]

				J. A. Fogarty, J. M. Muller-Delp, M. D. Delp, M. L. Mattox, M. H. Laughlin, and J. L. Parker Exercise Training Enhances Vasodilation Responses to Vascular Endothelial Growth Factor in Porcine Coronary Arterioles Exposed to Chronic Coronary Occlusion Circulation, February 10, 2004; 109(5): 664 - 670. [Abstract] [Full Text] [PDF]

				R. Tamarat, J.-S. Silvestre, S. Le Ricousse-Roussanne, V. Barateau, L. Lecomte-Raclet, M. Clergue, M. Duriez, G. Tobelem, and B. I. Levy Impairment in Ischemia-Induced Neovascularization in Diabetes: Bone Marrow Mononuclear Cell Dysfunction and Therapeutic Potential of Placenta Growth Factor Treatment Am. J. Pathol., February 1, 2004; 164(2): 457 - 466. [Abstract] [Full Text] [PDF]

				S. Dimmeler and M. Vasa-Nicotera Aging of progenitor cells: limitation for regenerative capacity? J. Am. Coll. Cardiol., December 17, 2003; 42(12): 2081 - 2082. [Full Text] [PDF]

				K. Yamamoto, T. Takahashi, T. Asahara, N. Ohura, T. Sokabe, A. Kamiya, and J. Ando Proliferation, differentiation, and tube formation by endothelial progenitor cells in response to shear stress J Appl Physiol, November 1, 2003; 95(5): 2081 - 2088. [Abstract] [Full Text] [PDF]

				A. Germani, A. Di Carlo, A. Mangoni, S. Straino, C. Giacinti, P. Turrini, P. Biglioli, and M. C. Capogrossi Vascular Endothelial Growth Factor Modulates Skeletal Myoblast Function Am. J. Pathol., October 1, 2003; 163(4): 1417 - 1428. [Abstract] [Full Text] [PDF]

				N. Nagaya, K. Kangawa, M. Kanda, M. Uematsu, T. Horio, N. Fukuyama, J. Hino, M. Harada-Shiba, H. Okumura, Y. Tabata, et al. Hybrid Cell-Gene Therapy for Pulmonary Hypertension Based on Phagocytosing Action of Endothelial Progenitor Cells Circulation, August 19, 2003; 108(7): 889 - 895. [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]

				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]

				P. Vajkoczy, S. Blum, M. Lamparter, R. Mailhammer, R. Erber, B. Engelhardt, D. Vestweber, and A. K. Hatzopoulos Multistep Nature of Microvascular Recruitment of Ex Vivo-expanded Embryonic Endothelial Progenitor Cells during Tumor Angiogenesis J. Exp. Med., June 16, 2003; 197(12): 1755 - 1765. [Abstract] [Full Text] [PDF]

				P. O. Bonetti, D. R. Holmes Jr, A. Lerman, and G. W. Barsness Enhanced external counterpulsation for ischemic heart disease: What's behind the curtain? J. Am. Coll. Cardiol., June 4, 2003; 41(11): 1918 - 1925. [Abstract] [Full Text] [PDF]

				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]

				P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]

				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]

				M. F. Bolontrade, R.-R. Zhou, and E. S. Kleinerman Vasculogenesis Plays a Role in the Growth of Ewing's Sarcoma in Vivo Clin. Cancer Res., November 1, 2002; 8(11): 3622 - 3627. [Abstract] [Full Text] [PDF]

				J. Thyberg Re-endothelialization Via Bone Marrow-Derived Progenitor Cells: Still Another Target of Statins in Vascular Disease Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1509 - 1511. [Full Text] [PDF]

				P. P. Young, A. A. Hofling, and M. S. Sands VEGF increases engraftment of bone marrow-derived endothelial progenitor cells (EPCs) into vasculature of newborn murine recipients PNAS, September 3, 2002; 99(18): 11951 - 11956. [Abstract] [Full Text] [PDF]

				S. Pislaru, S. P. Janssens, B. J. Gersh, and R. D. Simari Defining Gene Transfer Before Expecting Gene Therapy: Putting the Horse Before the Cart Circulation, July 30, 2002; 106(5): 631 - 636. [Full Text] [PDF]

				D. H. Walter, K. Rittig, F. H. Bahlmann, R. Kirchmair, M. Silver, T. Murayama, H. Nishimura, D. W. Losordo, T. Asahara, and J. M. Isner Statin Therapy Accelerates Reendothelialization: A Novel Effect Involving Mobilization and Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells Circulation, June 25, 2002; 105(25): 3017 - 3024. [Abstract] [Full Text] [PDF]

				T. T. Rissanen, I. Vajanto, M. O. Hiltunen, J. Rutanen, M. I. Kettunen, M. Niemi, P. Leppanen, M. P. Turunen, J. E. Markkanen, K. Arve, et al. Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 (KDR/Flk-1) in Ischemic Skeletal Muscle and Its Regeneration Am. J. Pathol., April 1, 2002; 160(4): 1393 - 1403. [Abstract] [Full Text] [PDF]

				S. B. Freedman and J. M. Isner Therapeutic Angiogenesis for Coronary Artery Disease Ann Intern Med, January 1, 2002; 136(1): 54 - 71. [Abstract] [Full Text] [PDF]

				T. Stevens, R. Rosenberg, W. Aird, T. Quertermous, F. L. Johnson, J. G. N. Garcia, R. P. Hebbel, R. M. Tuder, and S. Garfinkel NHLBI workshop report: endothelial cell phenotypes in heart, lung, and blood diseases Am J Physiol Cell Physiol, November 1, 2001; 281(5): C1422 - C1433. [Abstract] [Full Text] [PDF]

				E. M. Conway, D. Collen, and P. Carmeliet Molecular mechanisms of blood vessel growth Cardiovasc Res, February 16, 2001; 49(3): 507 - 521. [Full Text] [PDF]

				A. Kawamoto, H.-C. Gwon, H. Iwaguro, J.-I. Yamaguchi, S. Uchida, H. Masuda, M. Silver, H. Ma, M. Kearney, J. M. Isner, et al. Therapeutic Potential of Ex Vivo Expanded Endothelial Progenitor Cells for Myocardial Ischemia Circulation, February 6, 2001; 103(5): 634 - 637. [Abstract] [Full Text] [PDF]

				M. Gill, S. Dias, K. Hattori, M. L. Rivera, D. Hicklin, L. Witte, L. Girardi, R. Yurt, H. Himel, and S. Rafii Vascular Trauma Induces Rapid but Transient Mobilization of VEGFR2+AC133+ Endothelial Precursor Cells Circ. Res., February 2, 2001; 88(2): 167 - 174. [Abstract] [Full Text] [PDF]

				S. Dimmeler and A. M. Zeiher Endothelial Cell Apoptosis in Angiogenesis and Vessel Regression Circ. Res., September 15, 2000; 87(6): 434 - 439. [Abstract] [Full Text] [PDF]

				H. Iwaguro, J.-i. Yamaguchi, C. Kalka, S. Murasawa, H. Masuda, S.-i. Hayashi, M. Silver, T. Li, J. M. Isner, and T. Asahara Endothelial Progenitor Cell Vascular Endothelial Growth Factor Gene Transfer for Vascular Regeneration Circulation, February 12, 2002; 105(6): 732 - 738. [Abstract] [Full Text] [PDF]

				M. Vasa, S. Fichtlscherer, K. Adler, A. Aicher, H. Martin, A. M. Zeiher, and S. Dimmeler Increase in Circulating Endothelial Progenitor Cells by Statin Therapy in Patients With Stable Coronary Artery Disease Circulation, June 19, 2001; 103(24): 2885 - 2890. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Methods Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kalka, C. Articles by Asahara, T. Search for Related Content PubMed PubMed Citation Articles by Kalka, C. Articles by Asahara, T. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Stem Cells Related Collections Angiogenesis Peripheral vascular disease Gene therapy