on December 15, 2003
Published online before print December 15, 2003, doi: 10.1161/01.CIR.0000106906.56972.83
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© American Heart Association, Inc.
Basic Science Reports |
Estrogen-Mediated, Endothelial Nitric Oxide Synthase–Dependent Mobilization of Bone Marrow–Derived Endothelial Progenitor Cells Contributes to Reendothelialization After Arterial Injury
From the Division of Cardiovascular Research, St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass.
Correspondence to Douglas W. Losordo, MD, St Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail douglas.losordo{at}tufts.edu
Received March 5, 2003; de novo received September 12, 2003; revision received October 30, 2003; accepted October 31, 2003.
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Abstract |
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Background— We hypothesized that estrogen-induced acceleration of reendothelialization might be mediated in part by effects involving mobilization and incorporation of bone marrow–derived endothelial progenitor cells (EPCs).
Methods and Results— Carotid injury was induced in ovariectomized wild-type mice receiving either 17ß-estradiol or placebo. Estradiol treatment significantly accelerated reendothelialization of injured arterial segments within 7 days and resulted in a significant reduction of medial thickness 14 and 21 days after the injury. Significant increases in circulating EPCs 3 days after the injury were observed in the estradiol group compared with placebo-treated mice. These data were further supported by fluorescence-activated cell sorting analysis, which disclosed a significant increase in Sca-1/Flk-1–positive cells in estradiol versus control mice. To evaluate the effects of estradiol on bone marrow–derived EPC incorporation at sites of reendothelialization, carotid injury was established in ovariectomized wild-type mice transplanted with bone marrow from transgenic donors expressing ß-galactosidase transcriptionally regulated by the Tie-2 promoter. Significantly greater numbers of X-gal–positive cells were observed at reendothelialized areas in the estradiol group 3 days after injury as compared with placebo. Fluorescent immunohistochemistry 14 days after the injury documented a marked increase in cells expressing both ß-gal, indicating bone marrow origin and Tie-2 expression, and isolectin B4, also indicating endothelial lineage, in the estradiol group compared with control. In contrast, estradiol did not accelerate reendothelialization or augment EPC mobilization into the peripheral circulation after injury in endothelial nitric oxide synthase–deficient mice (eNOS-/-). Furthermore, estradiol exhibited direct stimulatory effects on EPC mitogenic and migration activity and inhibited EPC apoptosis.
Conclusions— Estradiol accelerates reendothelialization and attenuates medial thickening after carotid injury in part by augmenting mobilization and proliferation of bone marrow–derived EPCs and their incorporation into the recovering endothelium at the site of injury.
Key Words: estrogen • endothelium • arteries • nitric oxide synthase
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Introduction |
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Disruption of the anatomic and functional integrity of the endothelium has been postulated as a mechanism for the initiation of atherosclerosis.1 A corollary hypothesis is that restoration of endothelial integrity should inhibit atherogenesis. Accordingly, the finding that estradiol induces endothelial proliferation and migration2 mediated by the classic estrogen receptor3,4 suggests a potential mechanism by which estradiol might protect the vasculature. Indeed, mechanical disruption of the endothelium by balloon angioplasty in various animal models has been shown to result in the formation of a neointimal lesion,5,6 whereas agents that accelerate reendothelialization, including estradiol, have been shown to attenuate intimal hyperplasia.7,8
Recently, work in our laboratory9,10 and others11,12 has suggested that endothelial cells (ECs) adjacent to the site of balloon injury might not constitute the sole participants in endothelial recovery. These studies suggested that circulating cells, derived from the bone marrow and exhibiting certain features consistent with EC identity, were capable of being recruited to sites of arterial injury and contributing to reestablishing the neoendothelium. These cells, referred to as endothelial progenitors (EPCs) or circulating endothelial progenitors, have also been shown to participate in neovascularization in a variety of settings including ischemic tissue,10,13 tumors,14 and the retina.15 Moreover, preliminary studies in our laboratory indicated that these cells might be regulated by estradiol.16
Accordingly, we performed a series of investigations to test the hypothesis that estrogen accelerates reendothelialization by effects involving mobilization of bone marrow–derived EPCs.
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Methods |
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Mouse Carotid Injury
All procedures were performed in accordance with St Elizabeth’s Institutional Animal Care and Use Committee. Mice were anesthetized by intraperitoneal injection of 150 mg/kg ketamine for all surgical procedures. Eighty female FVB/N wild-type mice (Jackson Laboratory, Bar Harbor, Maine) were ovariectomized at 4 weeks of age and received either 90-day release 17ß-estradiol pellets (1.7 mg 17ß-estradiol, Innovative Research of America) or placebo-containing pellets (each n=40) implanted subcutaneously into the backs of the animals 4 weeks after the ovariectomy. This dose was used to achieve levels in the upper range of those occurring in nonpregnant premenopausal humans at midcycle and in the luteal phase of the normal menstrual cycle.17 These levels are
3-fold higher than occur in the nonpregnant mouse. We also used 24 bone marrow transplant (BMT) mice created by transplantation of bone marrow from transgenic mice (FVB/N-TgN{TIE2LacZ}, Jackson Laboratory) constitutively overexpressing ß-galactosidase regulated by the endothelial specific Tie-2 promoter, as previously described.18 In brief, female FVB/N wild-type mice were ovariectomized at 4 weeks age. One week after ovariectomy, recipient mice were lethally irradiated with 9.0 Gy, and BMT from the transgenic mice was performed. At 3 weeks after BMT, by which time the bone marrow of recipient mice was reconstituted with the transplanted bone marrow, recipient mice received subcutaneous 17ß-estradiol (n=12) or placebo (n=12) pellet implantation. Carotid artery injury was established both in wild-type and BMT animals 1 week after pellet implantation as described previously.19,20 Briefly, the bifurcation of the left carotid artery was exposed through a midline skin incision of the ventral aspect of the neck, with the use of a dissecting microscope; 6-0 silk sutures were placed around the common carotid and internal and external carotid arteries to temporarily restrict blood flow to the area of surgical manipulation. The artery was injured with a 0.014-inch-diameter flexible angioplasty wire, modified to create a barotraumatic/stretch injury, introduced into the external carotid artery and advanced to the common carotid artery. The wire was advanced and withdrawn 3 times to ensure a reliable effect. The total length of denuded common carotid artery was 4 mm from the bifurcation of carotid arteries in all animals. The wire was removed from the artery, the external carotid artery was permanently ligated, and the temporary ligatures were released to allow blood flow to be restored through the internal carotid artery. The connective tissue and subcutis were closed with continuous 7-0 monofilament suture, and the skin was then closed with the same procedure. Circulating 17ß-estradiol levels were measured 7 and 14 days after carotid injury with a commercially available enzyme-linked immunoassay (estradiol ELISA, Cayman Chemical Co, Inc), according to the manufacturer’s instructions.
Histological Assessment of Wild-Type Animals
To measure the reendothelialized area, wild-type animals were perfused in vivo with Evans blue dye (Sigma) 3, 5, 7, and 14 days after the injury, as described previously.19,20 Briefly, 50 µL of 5% Evans blue diluted with saline was injected into the heart with a 27-gauge needle 10 minutes before the animals were killed, followed by fixation by perfusion of 4% paraformaldehyde (PFA) for 5 minutes. Blood, saline, and fixative were removed through an incision in the right atrium. The common carotid artery was then harvested 4 mm from the carotid bifurcation; the artery was opened longitudinally and placed between slides with Fluoprep. The areas stained and unstained in blue and the total carotid artery area were measured, and the percentage areas were calculated by using the entire injured area, based on anatomic landmarks, as the baseline. For measurement of medial area, carotid arteries 14 and 21 days after the injury were embedded in paraffin after perfusion fixation with 4% PFA, and sections perpendicular to the long axis of the arteries were cut from the proximal and distal sections of the injured artery. Each section was stained with elastic trichrome. Morphometric analysis of digitalized images was performed with the use of NIH Image 1.61 software.
EPC Culture Assay
Total mononuclear cells were isolated from 500 µL of peripheral blood by density gradient centrifugation with Histopaque-1083 (Sigma) and cultured in phenol red–free EC basal medium (EBM, Clonetics) medium supplemented with 5% fetal bovine serum, antibiotics, and growth factors, as previously described.21 Four days after culture on 4-well glass slides coated with rat plasma vitronectin (Sigma) in 0.5% gelatin solution, EPCs, recognized as attaching spindle-shaped cells, were assayed by costaining with acetylated LDL (acLDL)-DiI (Biomedical Technologies) and FITC-conjugated Bandeiraea simplicifolia lectin I (Vector Laboratories), both of which are features characteristic of endothelial lineage.21 Double-positive cells, identified by fluorescence microscopy by an investigator blinded to treatment, were counted as EPCs in 15 randomly selected fields of each cultured slide. Acknowledging that this technique is not 100% specific for endothelial lineage cells, we performed an additional assay to evaluate EPC kinetics after arterial injury in estradiol-treated and untreated mice.
Fluorescence-Activated Cell Sorting Analysis
The viable mononuclear cell population was analyzed for the expression of Sca-1-FITC (Pharmingen) and Flk-1 (Santa Cruz) conjugated with the corresponding phycoerythrin-labeled secondary antibody (Sigma).22 Isotype-identical antibodies served as negative controls. Immunofluorescence-labeled cells were fixed with 2% paraformaldehyde and analyzed by quantitative flow cytometry with the use of a FACStar flow cytometer (Becton Dickinson) and Cell Quest Software counting 10 000 events per sample.
Cellular Identification of LacZ-Expressing Cells
The carotid arteries from BMT mice were harvested 3 and 14 days after the injury. X-gal staining was performed on whole mounted vessels to visualize and quantify bone marrow–derived Tie2/LacZ-positive endothelial lineage cells per square millimeter of surface area, as described previously.23 Target vessels from BMT mice were also embedded in OCT compound (Miles Scientific) and snap-frozen in liquid nitrogen for fluorescence microscopy immediately after the animals were killed. Immunohistochemical staining was performed with the use of antibodies prepared against rabbit anti–ß-galactosidase IgG (CORTEX Biochem) and the murine-specific EC marker, biotinylated isolectin B4 (Vector Laboratories).23
Endothelial Nitric Oxide Synthase–Deficient Mice
Four-week-old female endothelial nitric oxide synthase–deficient (eNOS-/-) mice and C57BL/6J mice as wild-type control mice were purchased from Jackson Laboratories. After ovariectomy, all mice received either 17ß-estradiol or a placebo-containing pellet implanted subcutaneously as above, and carotid injury was performed as described. Reendothelialization, assessed by in vivo perfusion with Evans blue dye, was performed 3 and 7 days after injury in eNOS-/- mice treated with or without 17ß-estradiol and in wild-type mice treated with 17ß-estradiol. EPC mobilization into the peripheral circulation, identified as Sca-1–positive and Flk-1–positive cells by FACS analysis, was assessed before injury and 3 and 7 days after the injury in eNOS-/- and wild-type mice treated with 17ß-estradiol.
Effects of Estradiol on Cultured EPC In Vitro (Mitogenic and Migration Activity, Antiapoptosis)
Mitogenic activity was assayed as described previously (CellTiter96 nonradioactive cell proliferation assay (Promega).21 Briefly, mouse EPCs were harvested after 7 days in culture and reseeded into a 96-well plate in phenol red–free EBM medium supplemented with 0.5% BSA overnight. 17ß-Estradiol diluted to serial concentrations (10-10, 10-9, 10-9 mol/L) was added to the wells for 48 hours before optical density measurement (562 nm). The EPC proliferation index was calculated by calibrating the density of cells without 17ß-estradiol to 1.0.
To investigate EPC migration activity, a modified Boyden chamber assay was performed as previously described.21 Briefly, 17ß-estradiol was diluted to the same serial concentrations in phenol red–free EBM media supplemented with 0.1% BSA in the bottom chamber, and mouse EPCs were reseeded in the upper chamber. The cells on the bottom of the filter, stained with Giemsa solution (Baxter Diagnostics) were counted manually in random fields in each well.
The proportion of apoptotic EPCs after serum starvation was quantified by manually counting pyknotic nuclei after 4'-6'-diaminidmo staining (DAPI, Roche), as described previously.24 In brief, cultured mouse EPCs (1x105 cells per well) underwent serum deprivation for 48 hours and were then incubated in phenol red–free medium alone or supplemented with 17ß-estradiol (10-8 mol/L) for 3 hours, after which DAPI-stained pyknotic nuclei were counted as a percentage of cells in each well. For DNA cleavage assays, the serum-starved EPCs (4x105) were incubated with or without 17ß-estradiol (10-8 mol/L) for 3 hours, and total DNA was extracted from the cells by using the Puregene DNA isolation kit (Gentra Systems). The pellet was resuspended in TE buffer (10 mmol/L Tris-HCl, pH 8.0; 1 mmol/L EDTA) and treated with DNase-free RNase for 1 hour at 37°C. DNA was ethanol-precipitated and resuspended in distilled water. Total DNA was electrophoretically fractionated on a 1.5% agarose gel and stained with ethidium bromide.25
All of the above in vitro studies were performed in triplicate.
Statistical Analysis
All values are expressed as mean±SEM. Statistical significance was evaluated by means of the Wilcoxon rank-sum test for comparisons between two groups. Multiple comparisons were performed through the use of ANOVA with Bonferroni’s correction. A value of P<0.05 was considered statistically significant.
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Results |
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Serum levels of 17ß-estradiol in the placebo group 7 and 14 days after the carotid injury were <2 pg/mL. In contrast, the levels in the estradiol group after 7 and 14 days after the injury were 580±55 and 559±62 pg/mL, respectively (P<0.01 versus placebo).
Effect of Estradiol on the Response to Injury in Wild-Type Animals
Figure 1A shows examples of arteries harvested 3, 5, and 7 days after injury from mice receiving estradiol versus placebo pellets. At all time points after injury, the estradiol-treated arteries showed a larger reendothelialized area as compared with the non–estradiol-treated arteries. Quantification demonstrated that estradiol treatment significantly accelerated reendothelialization compared with the placebo treatment, as has been shown previously in the rat and mouse (Figure 1B).8,26,27 The inner surface of the carotid artery in each group was completely reendothelialized 14 days after the injury. Also consistent with prior studies, estradiol significantly inhibited the injury-induced increase in medial area (Figure 1, C and D).28
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Effect of Estrogen on Circulating EPC Kinetics
Before carotid injury, the number of circulating EPCs was similar in the groups. However, the number of EPCs in the circulation of the estradiol group was significantly greater than in the placebo group 3 days after arterial injury (377±22 versus 306±26 cells/mm2, P<0.05, Figure 2A). Furthermore, the number of EPCs returned to baseline 7 days after injury in both groups.
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These data were further supported by FACS analysis for quantification of Sca-1/Flk-1–positive cells. Representative FACS analysis 3 and 7 days after injury in both groups is shown in Figure 2B, revealing a significant increase of EPCs in the estradiol group 3 days after injury as compared with the placebo group (12.1±2.0 versus 4.4±0.3%, P<0.05) (Figure 2C).
Enhanced Contribution of Bone Marrow–Derived EPCs to Reendothelialization
As shown in Figure 3A, a and b, whole-mounted X-gal–stained carotid arteries from the estradiol-treated mice displayed greater numbers of X-gal positive cells on the luminal surface than in the placebo-treated mice 3 days after the injury. Quantification of whole-mounted X-gal–stained specimens in the estradiol group revealed a significant increase in X-gal–positive cells 3 days after the injury as compared with the placebo group (34±6 versus 17±3 cells/mm2, P<0.05, Figure 3A, c). Furthermore, double-fluorescent immunohistochemistry for ß-galactosidase and biotinylated isolectin B4 was performed on frozen sections 14 days after injury to identify bone marrow–derived Tie2/LacZ–positive ECs. At the injury site, double-positive cells were detected with greater frequency in the endothelial monolayer in estradiol-treated mice (Figure 3B, a through d). Quantification of bone marrow–derived Tie2/LacZ–positive ECs at the injury site disclosed a significant 3-fold increase in the number of double-positive cells on the reendothelialized luminal surface in cross sections of estradiol-treated versus non–estradiol-treated mice (6.2±1.8 versus 2.2±0.4 cells/section, P<0.05)(Figure 3B, e). These data thus demonstrate that accelerated reendothelialization achieved with estradiol involves augmented EPC incorporation into the carotid artery neoendothelium.
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eNOS Is Required for Estradiol-Induced Acceleration of Reendothelialization
Figure 4A shows examples of carotid arteries harvested from eNOS-/- mice receiving estradiol or placebo pellets and from wild-type mice receiving estradiol pellets 3 days and 7 days after the injury. The reendothelialized areas were similar in eNOS-/- mice receiving estradiol or placebo pellet, whereas wild-type mice receiving estradiol pellets had a greater area reendothelialized than did the eNOS-/- mice receiving estradiol or placebo pellets (Figure 4A). Quantification demonstrated that estradiol treatment significantly accelerated reendothelialization in wild-type mice (Figure 1B) but had no effect in eNOS-/- mice (Figure 4B).
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The percentage of Flk-1/Sca-1–positive cells in the circulation in estradiol-treated wild-type and eNOS-/- mice, assessed by FACS analysis, was equivalent before the carotid injury (Figure 4C). However, the percentage of double-positive cells significantly increased 3 days after injury only in the wild-type mice receiving estradiol. Thus, estradiol failed to increase EPC numbers after arterial injury and failed to accelerate reendothelialization in the absence of eNOS expression.
Effect of Estradiol on EPC Mitogenesis, Migration, and Apoptosis
Mitogenic activity of EPCs was increased by estradiol at all but the lowest concentration of estradiol (10-10 mol/L) and displayed a dose response (control: 1.00±0.32, 10-10 mol/L: 1.05±0.02, 10-9 mol/L: 1.32±0.03, 10-8 mol/L: 1.17±0.02, P<0.001, Figure 5A). Estradiol also induced EPC migration in a dose-dependent manner (control: 901±50, 10-10 mol/L: 1446±146, 10-9 mol/L: 1468±138, 10-8 mol/L estradiol: 1799±38 cells/mm2, P<0.01, Figure 5B). Moreover, estradiol had an antiapoptotic effect on EPCs when assayed on the basis of counting of apoptotic cells (8±3 versus 19±6%, P<0.01, Figure 5C, a to c), as has been shown previously in mature ECs.29 The antiapoptotic effects of estradiol were also verified by documenting inhibition of DNA fragmentation in cultured EPCs subjected to serum starvation (Figure 5C).
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Discussion |
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The present study provides evidence that estrogen mobilizes circulating EPCs from the bone marrow and that these cells incorporate into the neoendothelium, thereby contributing to reendothelialization after arterial injury. This effect is shown to be dependent on eNOS expression, as both EPC mobilization and acceleration of reendothelialization are absent in estradiol-treated eNOS-null mice. Moreover, these data disclose that estradiol has similar direct effects on EPCs, as have been documented in mature ECs,2,29 inducing proliferation and migration and inhibiting apoptosis. These findings are consistent with those recently reported by Strehlow et al27 and also add the important finding of an eNOS-dependent mechanism for the effects of estradiol on EPCs and endothelial recovery. Most notably, the present findings suggest that enhanced EPC mobilization and recruitment to sites of arterial injury may be the central feature of the beneficial effect of estradiol.
It has long been thought that endothelial regeneration in response to arterial injury was a local process involving endothelial proliferation and migration from intact ECs adjacent to the site of injury. The acceleration of reendothelialization by estrogen after injury has likewise been interpreted to develop as a result of these same mechanisms. These data suggest that an alternative mechanism may be critical to this process.
EPCs have been isolated from circulating mononuclear cells in peripheral blood and shown to incorporate into foci of neovascularization of adults, consistent with the notion of postnatal vasculogenesis.9,11,30 These bone marrow–derived EPCs are mobilized endogenously in response to tissue ischemia and/or exogenously by cytokine stimulation. Vascular endothelial growth factor and granulocyte macrophage-colony stimulating factor can mobilize EPCs from bone marrow into the peripheral circulation.10,21 The present data show estradiol to be capable of modulating EPC kinetics under pathological circumstances. The full implications of this finding for our understanding of the effects of estradiol on vascular biology remain to be determined. It is, however, interesting to note the parallel between the effect of estradiol and that of statins. Statins have been shown to reduce coronary event rates and to accelerate endothelial recovery after injury, in part through mobilization and incorporation of EPCs at the site of injury.23 These actions of statins are mediated through phosphorylation of the protein kinase Akt. Moreover, statins have been shown to modulate EPC proliferation, migration, and survival31,32 and to accelerate reendothelialization by a mechanism involving EPCs.23 In this context, it is interesting to note that estradiol has also been shown to activate Akt signaling, suggesting one possible mechanism for modulation of EPCs.33
Given the above findings, the central role of Akt signaling in eNOS activity and the regulation of eNOS and NO by estradiol,34,35 we considered the possibility that EPC mobilization by estradiol might require NO-mediating signaling. We evaluated reendothelialization and EPC kinetics after the injury in eNOS-/- mice and found that the absence of eNOS essentially nullified estradiol-induced mobilization of EPCs and blocked the acceleration of endothelial recovery seen in wild-type mice treated with estradiol. These results suggested that the presence of eNOS might be a key factor of estradiol-induced, EPC-mediated reendothelialization.
The present study reveals that estrogen can augment EPC mobilization into sites of neovascularization in adult organs under pathological conditions. This process appears to require eNOS; however, the precise mechanism by which estrogen enhances EPC mobilization and incorporation remains to be defined. In addition, our data suggest that EPCs may provide a major contribution in the salutary effect of estradiol on endothelial recovery after arterial injury.
In conclusion, estrogen augments mobilization and proliferation of bone marrow–derived EPCs, which contribute to accelerate reendothelialization and attenuate vascular remodeling at sites of arterial injury. These results provide novel insights into potential mechanisms of estrogen effects on vascular biology.
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Acknowledgments |
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This work was supported in part by the following grants: National Institutes of Health HL-63695 and HL-57516 (Dr Losordo).The authors gratefully acknowledge the secretarial assistance of Mickey Neely and the technical support of Ingrid Johnson in the preparation of the manuscript.
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References |
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N. Werner and G. Nickenig Sex Hormones Save Our Skin: The Vascular Networking of Estrogen Circ. Res., January 30, 2009; 104(2): 135 - 137. [Full Text] [PDF]
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K. Kondo, S. Shintani, R. Shibata, H. Murakami, R. Murakami, M. Imaizumi, Y. Kitagawa, and T. Murohara Implantation of Adipose-Derived Regenerative Cells Enhances Ischemia-Induced Angiogenesis Arterioscler Thromb Vasc Biol, January 1, 2009; 29(1): 61 - 66. [Abstract] [Full Text] [PDF]
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L. Lam Shang Leen, C. Filipe, A. Billon, B. Garmy-Susini, S. Jalvy, F. Robbesyn, D. Daret, C. Allieres, S. R. Rittling, N. Werner, et al. Estrogen-Stimulated Endothelial Repair Requires Osteopontin Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2131 - 2136. [Abstract] [Full Text] [PDF]
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I. Spyridopoulos, S. Fichtlscherer, R. Popp, S. W. Toennes, B. Fisslthaler, T. Trepels, A. Zernecke, E. A. Liehn, C. Weber, A. M. Zeiher, et al. Caffeine Enhances Endothelial Repair by an AMPK-Dependent Mechanism Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1967 - 1974. [Abstract] [Full Text] [PDF]
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A. Aicher, O. Kollet, C. Heeschen, S. Liebner, C. Urbich, C. Ihling, A. Orlandi, T. Lapidot, A. M. Zeiher, and S. Dimmeler The Wnt Antagonist Dickkopf-1 Mobilizes Vasculogenic Progenitor Cells via Activation of the Bone Marrow Endosteal Stem Cell Niche Circ. Res., October 10, 2008; 103(8): 796 - 803. [Abstract] [Full Text] [PDF]
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A. Caporali, E. Pani, A. J.G. Horrevoets, N. Kraenkel, A. Oikawa, G. B. Sala-Newby, M. Meloni, B. Cristofaro, G. Graiani, A. S. Leroyer, et al. Neurotrophin p75 Receptor (p75NTR) Promotes Endothelial Cell Apoptosis and Inhibits Angiogenesis: Implications for Diabetes-Induced Impaired Neovascularization in Ischemic Limb Muscles Circ. Res., July 18, 2008; 103(2): e15 - e26. [Abstract] [Full Text] [PDF]
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S. Dimmeler and A. Leri Aging and Disease as Modifiers of Efficacy of Cell Therapy Circ. Res., June 6, 2008; 102(11): 1319 - 1330. [Abstract] [Full Text] [PDF]
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A. Zampetaki, J. P. Kirton, and Q. Xu Vascular repair by endothelial progenitor cells Cardiovasc Res, June 1, 2008; 78(3): 413 - 421. [Abstract] [Full Text] [PDF]
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S. Purhonen, J. Palm, D. Rossi, N. Kaskenpaa, I. Rajantie, S. Yla-Herttuala, K. Alitalo, I. L. Weissman, and P. Salven Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth PNAS, May 6, 2008; 105(18): 6620 - 6625. [Abstract] [Full Text] [PDF]
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G. P. Fadini, S. de Kreutzenberg, M. Albiero, A. Coracina, E. Pagnin, I. Baesso, A. Cignarella, C. Bolego, M. Plebani, G. B. Nardelli, et al. Gender Differences in Endothelial Progenitor Cells and Cardiovascular Risk Profile: The Role of Female Estrogens Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 997 - 1004. [Abstract] [Full Text] [PDF]
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J. Tongers, J.-M. Knapp, M. Korf, T. Kempf, A. Limbourg, F. P. Limbourg, Z. Li, D. Fraccarollo, J. Bauersachs, X. Han, et al. Haeme oxygenase promotes progenitor cell mobilization, neovascularization, and functional recovery after critical hindlimb ischaemia in mice Cardiovasc Res, May 1, 2008; 78(2): 294 - 300. [Abstract] [Full Text] [PDF]
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W. D. Nelson, A. G. Zenovich, H. C. Ott, C. Stolen, G. J. Caron, A. Panoskaltsis-Mortari, S. A. Barnes III, X. Xin, and D. A. Taylor Sex-Dependent Attenuation of Plaque Growth After Treatment With Bone Marrow Mononuclear Cells Circ. Res., December 7, 2007; 101(12): 1319 - 1327. [Abstract] [Full Text] [PDF]
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M. E. Kleinman, M. R. Greives, S. S. Churgin, K. M. Blechman, E. I. Chang, D. J. Ceradini, O. M. Tepper, and G. C. Gurtner Hypoxia-Induced Mediators of Stem/Progenitor Cell Trafficking Are Increased in Children With Hemangioma Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2664 - 2670. [Abstract] [Full Text] [PDF]
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H. Masuda, C. Kalka, T. Takahashi, M. Yoshida, M. Wada, M. Kobori, R. Itoh, H. Iwaguro, M. Eguchi, Y. Iwami, et al. Estrogen-Mediated Endothelial Progenitor Cell Biology and Kinetics For Physiological Postnatal Vasculogenesis Circ. Res., September 14, 2007; 101(6): 598 - 606. [Abstract] [Full Text] [PDF]
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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]
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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]
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K. Moriarty, K. H. Kim, and J. R. Bender Estrogen Receptor-Mediated Rapid Signaling Endocrinology, December 1, 2006; 147(12): 5557 - 5563. [Abstract] [Full Text] [PDF]
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H. Hamada, M. K. Kim, A. Iwakura, M. Ii, T. Thorne, G. Qin, J. Asai, Y. Tsutsumi, H. Sekiguchi, M. Silver, et al. Estrogen Receptors {alpha} and {beta} Mediate Contribution of Bone Marrow-Derived Endothelial Progenitor Cells to Functional Recovery After Myocardial Infarction Circulation, November 21, 2006; 114(21): 2261 - 2270. [Abstract] [Full Text] [PDF]
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V. Fontaine, C. Filipe, N. Werner, P. Gourdy, A. Billon, B. Garmy-Susini, L. Brouchet, F. Bayard, H. Prats, T. Doetschman, et al. Essential Role of Bone Marrow Fibroblast Growth Factor-2 in the Effect of Estradiol on Reendothelialization and Endothelial Progenitor Cell Mobilization Am. J. Pathol., November 1, 2006; 169(5): 1855 - 1862. [Abstract] [Full Text] [PDF]
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K.-i. Sasaki, C. Heeschen, A. Aicher, T. Ziebart, J. Honold, C. Urbich, L. Rossig, U. Koehl, M. Koyanagi, A. Mohamed, et al. Ex vivo pretreatment of bone marrow mononuclear cells with endothelial NO synthase enhancer AVE9488 enhances their functional activity for cell therapy PNAS, September 26, 2006; 103(39): 14537 - 14541. [Abstract] [Full Text] [PDF]
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J. Chen and M. S. Goligorsky Premature senescence of endothelial cells: Methusaleh's dilemma Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1729 - H1739. [Abstract] [Full Text] [PDF]
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A. Iwakura, S. Shastry, C. Luedemann, H. Hamada, A. Kawamoto, R. Kishore, Y. Zhu, G. Qin, M. Silver, T. Thorne, et al. Estradiol Enhances Recovery After Myocardial Infarction by Augmenting Incorporation of Bone Marrow-Derived Endothelial Progenitor Cells Into Sites of Ischemia-Induced Neovascularization via Endothelial Nitric Oxide Synthase-Mediated Activation of Matrix Metalloproteinase-9 Circulation, March 28, 2006; 113(12): 1605 - 1614. [Abstract] [Full Text] [PDF]
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K. Satoh, Y. Kagaya, M. Nakano, Y. Ito, J. Ohta, H. Tada, A. Karibe, N. Minegishi, N. Suzuki, M. Yamamoto, et al. Important Role of Endogenous Erythropoietin System in Recruitment of Endothelial Progenitor Cells in Hypoxia-Induced Pulmonary Hypertension in Mice Circulation, March 21, 2006; 113(11): 1442 - 1450. [Abstract] [Full Text] [PDF]
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G. Garin, M. Mathews, and B. C. Berk Tissue-Resident Bone Marrow-Derived Progenitor Cells: Key Players in Hypoxia-Induced Angiogenesis Circ. Res., November 11, 2005; 97(10): 955 - 957. [Full Text] [PDF]
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J. Molnar, S. Yu, N. Mzhavia, C. Pau, I. Chereshnev, and H. M. Dansky Diabetes Induces Endothelial Dysfunction but Does Not Increase Neointimal Formation in High-Fat Diet Fed C57BL/6J Mice Circ. Res., June 10, 2005; 96(11): 1178 - 1184. [Abstract] [Full Text] [PDF]
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A. Aicher, A. M. Zeiher, and S. Dimmeler Mobilizing Endothelial Progenitor Cells Hypertension, March 1, 2005; 45(3): 321 - 325. [Abstract] [Full Text] [PDF]
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