Published online before print December 14, 2006, doi: 10.1161/01.ATV.0000254812.23238.2b
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© 2007 American Heart Association, Inc.
Vascular Biology |
Endothelial E-Selectin Potentiates Neovascularization via Endothelial Progenitor Cell–Dependent and –Independent Mechanisms
From Department of Cardiovascular Medicine (Y.N., M.I.), Tokyo Medical and Dental University, School of Medicine, Tokyo, Japan; Department of Medical Biochemistry (Y.N., M.Y., N.N.), Tokyo Medical and Dental University, School of Medicine, Tokyo, Japan; Department of Regenerative Medicine (H.I., H.M., T.A.), Tokai University, School of Medicine, Kanagawa, Japan.
Correspondence to Masayuki Yoshida, 1-5-45,Yushima D9, Bunkyo-ku, Tokyo, 113-8519 Japan. E-mail masavasc{at}tmd.ac.jp
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Abstract |
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Background— Although potential participation of bone marrow-derived circulating endothelial progenitor cells (EPCs) to neoangiogenesis has been proposed, the precise molecular mechanisms of EPC recruitment to vascular endothelium has not been fully elucidated.
Methods and Results— Peripheral blood mononuclear cells were isolated from healthy volunteers and cultured for 7 days to obtain EPCs. Tumor necrosis factor-
–activated human umbilical vein endothelial cells (HUVECs) supported significantly more rolling and adhesion of EPCs compared with inactivated HUVEC monolayer. Pretreatment of activated HUVEC with an adhesion-blocking mAb to E-selectin significantly reduced EPCs adhesion to HUVECs. When HUVECs were transduced with a recombinant adenovirus of E-selectin (AdRSVE-sel) or that of ß-galactosidase (AdRSVLacZ), E-selectin-transduced but not LacZ-transduced HUVECs exhibited significantly more EPC rolling as well as adhesion. Further, effect of AdRSVE-sel or AdRSVLacZ was examined in mouse hind limb ischemic model. AdRSVE-sel–transduced mice showed significantly less limb necrosis and higher laser Doppler ratio when compared with AdRSVLacZ-transduced mice. Interestingly, blood flow recovery of ischemic limb observed in AdRSVE-sel–transduced mice was more prominent when combined with EPC administration compared with that of AdRSVLacZ-transduced mice.
Conclusions— Endothelial E-selectin plays a crucial role in EPC–endothelial interaction in vitro. The importance of E-selectin was also confirmed in vivo even in the absence of exogenous EPC. These data provide molecular background for novel cell-based therapy for ischemic atherosclerosis.
Although potential participation of bone marrow-derived circulating endothelial progenitor cells (EPCs) to neoangiogenesis has been proposed, the precise molecular mechanisms of EPC recruitment to vascular endothelium has not been fully elucidated.
Key Words: angiogenesis • adhesion molecule • endothelial cell
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Introduction |
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Recent studies have provided ample evidence that vasculogenesis, the formation of new blood vessels by differentiation of endothelial cells from their precursors, may occur after embryonic development. The identification of endothelial progenitor cells (EPCs) in circulating blood in postnatal subjects and their contribution to the formation of new blood vessels1–11 has drawn attention to their potential for therapeutic application. Although a study that used an ischemic animal model12 and carefully conducted clinical13 studies have documented the efficacy of the introduction of EPCs in ischemic tissues, the molecular mechanisms responsible for EPC recruitment into mature preexisting blood vessels are not fully understood. Several growth factors, including vascular endothelial growth factor,2 stem cell growth factor,9 and granulocyte-macrophage colony-stimulating factor,3 have been reported to be involved in the regulation of endothelial differentiation and migration to form functional vessels. However, the interaction between circulating EPCs and mature blood endothelial cells, presumably a critical biological event during the initial phase of vasculogenesis, has not been extensively studied. In some studies, the number of exogenous EPCs present in the ischemic tissue has been reported to be not as much at 28 days as compared with 1 day after injury, suggesting that not only EPC but also the soluble factor they secreted or expressed may also be important to facilitate neovasculogeneisis.14 To form properly assembled blood vessels, EPC orchestrate complex cell–cell adhesive interactions by coordinated actions of adhesion molecules and their ligands expressed on both EPC and preexisting endothelial cells.
E-selectin, a member of selectin family of adhesion molecules, is expressed primarily on activated vascular endothelium and facilitates rolling and adhesion of neutrophils, monocytes, and a subset of T lymphocytes.15 In addition to its role in acute and chronic inflammation, E-selectin has been shown to participate in ischemia/reperfusion injury in humans16 and, more importantly, E-selectin and its ligands have been reported to be involved in angiogenesis.17 In the present study, we used a well-defined parallel plate flow chamber apparatus and demonstrated that E-selectin expressed on activated endothelial cells plays a major role in rolling and adhesion of EPC in vitro. That initial observation was confirmed by use of a recombinant adenoviral vector of E-selectin. Our in vitro results were confirmed in vivo by using an ischemic hind limb model. Our findings indicate that E-selectin is a major adhesion receptor on preexisting endothelial cells that function to initiate postnatal neo-angiogenesis. Further, overexpression of E-selectin may be useful for therapeutic usage of EPCs, the current availability of which limits potential clinical outcomes.
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Methods |
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EPC Culture and Reagents
Peripheral blood mononuclear cells from human volunteers were plated on human fibronectin coated (Sigma) culture dishes and maintained in endothelial cell basal medium-2 (Clonetics) supplemented with 5% fetal bovine serum, human vascular endothelial growth factor-A, human fibroblast growth factor-2, human epidermal growth factor, insulin-like growth factor-1, and ascorbic acid, as previously described.1,18 After 4 days of culture, nonadherent cells were removed by washing with phosphate-buffered saline, then cultured 3 more days before use in a simulated flow assay.
Flow-Cytometric Analysis of EPCs
After 7 days of culture, adherent cells were detached and incubated first with the indicated primary antibodies on ice, then washed twice with RPMI 1640 containing 5% fetal bovine serum. Next, they were incubated with a fluorescein isothiocyanate-labeled goat anti-mouse antibody. Fluorescence was analyzed using a fluorescence-activated cell sorter Caliber (Beckton-Dickinson).
Adenovirus Transduction of HUVECs
In some experiments, after a 24-hour incubation on coverslips, HUVECs were transduced using a recombinant adenovirus of human E-selectin (AdRSVE-sel)19 or that of ß-galactosidase (AdRSVLacZ)20 at an MOI of 100, 72 hours before use in an EPC flow assay, as described previously.21
Adhesion Assay Under Laminar Flow
Apparatus Design
The parallel-plate flow chamber used was previously described in detail.22 Briefly, the chamber was composed of 2 aluminum steel plates separated by a 200-µm-thick silastic gasket, and the flow channel was formed by removal of a 2.5x15-mm rectangular section from the gasket. Predetermined levels of flow were applied to the HUVEC monolayer by drawing the perfusion medium (D-PBS containing 0.2% human serum albumin) through the channel with a syringe pump (model 44; Harvard Apparatus). A plastic heating plate (Tokai Hit Co) was mounted on the stage of an inverted microscope (IX50; Olympus) to maintain the temperature at 37°C. The channel flow could then be approximated as a 2-dimensional fully developed laminar flow with a simple parabolic velocity profile.
Experimental Application
HUVECs were isolated for use in the flow assay, and then after 2 or 3 passages were plated onto 22-mm fibronectin coated glass cover slips and subjected to the flow chamber. Flow assay endothelial monolayers on coverslips were stimulated with tumor necrosis factor- (10 ng/mL) and positioned in the flow chamber, which was mounted on an inverted microscope. Each monolayer was perfused for 3 minutes with perfusion medium and examined carefully to verify that it was confluent. Then, EPCs were diluted in the perfusion medium to 105 cells/mL and drawn through the chamber at a controlled flow rate to generate a calculated wall shear stress of 1.0 dyne/cm2 for 10 minutes. The entire period of perfusion was recorded on videotape using a digital video recorder containing a time generator. Captured images were then transferred to a computer for image analysis to determine the number of rolling and adherent EPC in 5 to 10 randomly selected 20x microscopic fields for each experiment. Cells were considered to be adherent after 10 seconds of stable contact with the monolayer. Rolling EPCs were easily recognized, as their velocity was much slower (up to 80 µm/second) than that of free-flowing cells.
In some experiments, the following antibodies were used to block EPC adhesion to HUVEC monolayers: mouse anti-E-selectin mAb (7A9), mouse anti-intercellular adhesion molecule-1 (ICAM-1) mAb (Hu5/3), mouse anti-vascular cell adhesion molecule (VCAM)-1 (BBIG-V), mouse anti-sLx (KM-93), mouse anti-PSGL-1 (KPL-1), mouse anti CD18 (MEM48).
Mouse Hind limb Ischemia Model
All animal procedures were performed in accordance with guidelines provided by the Tokyo Medical and Dental University Institutional Animal Care and Use Committee. Athymic nude mice (Crea, Japan), 8 to 9 weeks old and 17 to 20 grams in weight, were used. First, AdRSVE-sel or AdRSVLacZ (at 1x1010 pfu/limb) was injected into a lower limb of 19 mice. Seventy-two hours later, each mouse was anesthetized intraperitoneally with 160 mg/kg of pentobarbital for operative ligation of a femoral artery and vein, as previously described.4,13 In some experiments, EPCs at 1x105, 20% of the optimal number reported previously,4,13 in 100 µL of endothelial cell basal medium-2 media without any growth factors were injected into the ischemic limb muscle of the mice immediately after the ligation procedure. To determine the fate of the transplanted EPCs, 4 mice from each group received EPCs marked with fluorescent carbocyanine DiI dye (Molecular Probes), as previously described.23 In brief, suspended EPCs were washed with phosphate-buffered saline and incubated with DiI at a concentration of 2.5 µg/mL of phosphate-buffered saline for 5 minutes at 37°C, then 15 minutes at 4°C. After 2 washings in phosphate-buffered saline, the cells were suspended in endothelial cell basal medium-2 medium. Further, 30 minutes before these mice were euthanized, they received an intravenous injection of 50 µg of Bandeiraea simplicifolia lectin 1 (BS-1) conjugated with fluorescein isothiocyanate (Vector Laboratories).
Physiological Assessment of Animals
Laser Doppler perfusion imaging (Moor Instruments) was used to record blood flow 28 days after surgery, as previously described.23 In the digital color-coded images, the red hue indicated regions with maximum perfusion, whereas medium perfusion levels were shown as yellow and low levels as blue. The resulting images also displayed absolute values in readable units. For quantification, the ratio of readable units between ischemic and nonischemic hind limbs was determined.
Histological Assessment of Mouse Tissues
Vascular density in sections taken from the ischemic hind limbs was evaluated at the microvascular level using a light microscope. Tissue sections from the lower calf muscles of ischemic limbs were harvested on day 28, then muscle samples were embedded in OCT compound (Miles), snap-frozen in liquid nitrogen (LN2), and cut into 5-µm-thick sections. A total of 20 different fields were randomly selected and the number of capillaries was counted at 40x magnification. Immunohistochemical analysis of human E-selectin was carried out using anti human E-selectin mAb (7A9) as a primary antibody. MOM immunodetection kit (Vector Laboratories) was used to specifically localize mouse primary antibody (7A9) on mouse tissues following manufacturer’s instruction.
Statistical Analysis
All results were expressed as mean±SEM. Statistical significance was evaluated using a paired Scheffé t test or one-way ANOVA with Tukey post hoc test. A value of P<0.05 was considered to denote statistical significance.
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Results |
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Characterization of Human EPCs
In preliminary experiments, we confirmed the surface expression of markers for endothelial cells (CD34, CD31, and vascular endothelial growth factor receptor 2) in EPCs after 7 days of culture (data not shown). We also examined the uptake of DiI acetylated LDL and colony formation by EPCs to confirm that they had an endothelial lineage (data not shown). Based on those basic characterizations, we used EPCs after 7 days of culture in the following experiments.
Activation With Tumor Necrosis Factor- Increased EPC Rolling and Adhesion to Vascular Endothelium Under Physiological Flow Conditions
To monitor the adhesive interactions of EPCs, we utilized a parallel plate flow chamber system, which was initially designed to investigate leukocyte–endothelial interactions under physiological conditions.22,24 When EPCs were perfused over a monolayer of inactivated HUVECs, virtually no interaction was observed. In contrast, when HUVEC monolayers were activated with tumor necrosis factor-, a cytokine that is strongly upregulated during inflammation, including that in the ischemic vasculature, EPCs showed significant rolling and adhesion (Figure 1A and 1B). A time-kinetic analysis revealed that maximum induction of EPC rolling and adhesion occurred at 4 hours of stimulation with tumor necrosis factor-. Similarly, rolling and adhesion of EPCs were observed when HUVECs were stimulated with IL-1ß (10 U/mL, data not shown). Interestingly, when EPCs were stimulated with tumor necrosis factor, EPC adhesion to HUVECs was not induced (Figure 1C).
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To determine the adhesion molecules responsible for the observed interaction with EPCs HUVEC monolayers were pre-incubated with function blocking antibodies against E-selectin (7A9), ICAM-1 (Hu5/3), and VCAM-1 (BBIGV1), and the results were compared with those with a binding control mAb (w6/32). As shown in Figure 2A, pretreatment with 7A9, but not the others, significantly blocked the rolling and adhesion of EPCs to HUVECs, suggesting a potential role for E-selectin in the recruitment of EPCs to HUVEC monolayers.22
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SLx and PSGL-1 Were Not Involved in Initial Adhesive Interactions of EPCs to HUVEC Monolayers
Next, we investigated the potential ligands expressed on EPCs that interact with E-selectin in HUVEC monolayers. As previously reported, sialyl Lewis X (sLx), a carbohydrate has been known to bind to E-selectin.25 Further, P-selectin glycoprotein 1 (PSGL-1), a putative ligand for P-selectin, has also been shown to bind E-selectin.26 Although these antibodies were confirmed to inhibit monocyte adhesion to activated HUVECs (sLx, 37.05% reduction; PSGL-1 35.1% reduction; Figure 2B upper right column), the EPC endothelial interaction was not blocked by antibodies against sLx or PSGL-1 (Figure 2B).
Overexpression of E-Selectin Without Cytokine Stimulation Induced EPC Recruitment to HUVEC Monolayer
To verify the involvement of E-selectin in the adhesive interaction of EPCs with a HUVEC monolayer, we transduced HUVECs with a recombinant adenoviral vector of E-selectin (AdRSVE-sel) and compared the results to those transduced with a recombinant adenovirus expressing ß-galactosidase (AdRSVLacZ). Both adenoviral vectors were transduced at an MOI of 100 and an adhesion assay under flow was performed 72 hours after transduction. As shown in Figure 3, AdRSVE-sel–transduced HUVECs supported significantly greater levels of rolling and adhesion as compared with those transduced with AdRSVLacZ. Further, the inhibition of EPC adhesion seen after pretreatment with 7A9 confirmed the involvement of E-selectin in HUVECs transduced with the adenoviral vectors.
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Role of E-Selectin in EPC Transplantation in Murine Ischemic Hind limb Model
The potential role of E-selectin in neovascularization in vivo was investigated using a murine hind limb ischemia model. An intramuscular administration of AdRSVE-sel or AdRSVLacZ (1x1010pfu/limb) was injected into the left limb muscle 72 hours before femoral artery excitation and neovascularization was examined without EPC injection. As shown in Figure 5A, AdRSVE-sel was able to potentiate neovascularization even in the absence of exogenous EPCs. Perfusion ratio of ischemic limb was recovered up to 75% of noninjured contra lateral limb at 28 days after ischemia (Figure 4B). However, perfusion ratio of ischemic limb in AdRSVLacZ-transduced mice was much lower (38.94% of contra lateral limb; Figure 4B). To validate the contribution of endogenous progenitor cells in this process, immunohistochemical localization of CD34-positive cells at the site of ischemia was examined. As shown in (Figure 4C), clusters of CD34-positive cells were found only in AdRSVE-sel–transduced but not AdRSVLacZ-transduced mouse, suggesting their contribution to neovascularization. The expression of exogenous E-selectin was confirmed with a fluorescent immunohistochemical staining using anti human E-selectin mAb 7A9 (Figure 4D).
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We further investigated a role of E-selectin in neovascularization with EPC transplantation. One day after operative excision of a left femoral artery from each mouse, EPC at 1x105 (
20% of the optimal number of EPCs used in previous studies, which was insufficient to induce optimal neovascularization13) were injected into each ischemic limb. Examination of hind limb perfusion by laser Doppler perfusion imaging was performed on days 0 and 28, and the significant reduction of perfusion seen on day 0 confirmed the effectiveness of our ischemic procedure (Figure 5A, middle column). On day 28, the ratio of ischemic to normal blood flow in mice injected with AdRSVE-sel was strikingly improved, as compared with those injected with AdRSVLacZ (Figure 5A, right column). The blood flow of AdRSVE-sel–injected animal was recovered to the level of baseline. This improvement in blood flow in AdRSVE-sel–injected animal was also validated in representative photos (Figure 5B). Enhanced neovascularization in mice overexpressing E-selectin after EPC transplantation resulted in a significant improvement of tissue salvage, despite frequent auto-amputation of the ischemic limb attributable to the inherent impairment of neovascularization in athymic nude mice. In mice that received AdRSVLacZ, limb salvage (score 0 in Figure 5C) was achieved in only 1 of 9 animals, whereas extensive limb necrosis (score 4 and 5) developed in 4 of the remaining 8. In contrast, successful limb salvage (score 0) was achieved in 5 of the 10 mice that received AdRSVE-sel and limb necrosis (score 4) was limited to 1 (Figure 5C). A histological examination on day 28 revealed that capillary density in mice transduced with AdRSVE-sel plus EPC transplantation was significantly higher than in mice transduced with AdRSVLacZ and EPC transplantation (Figure 5D). To confirm the homing and incorporation of administered EPC in the sites of neovascularization, EPC labeled with fluorescent carbocyanine DiI dye were injected intramuscularly after excision of a left femoral artery. As shown in (Figure 5E), skeletal muscle sections prepared from the ischemic hind limbs 3 days after the mice received AdRSVE-sel exhibited an accumulation of EPCs (red cluster) in areas surrounding the injection site. Such accumulations of injected EPCs were not observed in sections from mice that received AdRSVLacZ (Figure 5E).
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Discussion |
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Our results demonstrated a potential role of endothelial E-selectin in the recruitment of EPC to facilitate neovascularization in ischemic tissues in vitro and in vivo. The present findings also showed the molecular requirements for the initial interaction of EPC and mature pre-existing endothelium. After identification of EPCs in the circulation of human adults, numerous reports have indicated the potential importance and therapeutic application of these cells in vivo using animal models of ischemia.1 Thus far, broad attention has been given to angiogenic enzymes, growth factors, and their receptors; however, the direct interaction of these progenitor cells to form blood vessels also requires cell adhesion molecules.27
Although the mechanisms responsible for leukocyte–endothelial interaction have been hypothesized, the precise molecular mechanisms involved with the initial EPC–endothelial interactions have yet to be investigated thoroughly. We found that E-selectin expression is necessary and sufficient to capture circulating EPC to a mature endothelial monolayer. Our findings are in agreement with previous observations that have focused on leukocyte–endothelial interactions in vivo15 and confirm the existence of similar adhesive properties in interacting vascular endothelial cells. The interaction of leukocytes to activated endothelial cells starts with the leukocytes rolling on the endothelial monolayer, which is primarily supported by the selectin family of adhesion molecules, after which they stably adhere via integrin and ICAM-1/VCAM-1 interactions. The present findings are the first to show that EPCs also follow the same adhesive interaction cascade. However, it is intriguing that mAbs against ICAM-1 and VCAM-1, adhesion molecules important for the stable adhesion of leukocytes in the presence of flow, failed to block the adhesion under our assay conditions. This result may imply the importance of other adhesion molecules, including novel ones, in this step of the adhesion cascade, which is different from what is known regarding leukocytes. In addition, the failure of antibodies against sLx or PSGL-1 to block the E-selectin dependent adhesion of EPCs suggests the role of an unknown ligand on the surface of EPCs and, considering its relatively broad ligand specificity,28,29 the contribution of known ligands with E-selectin should not be neglected.
The potential role of E-selectin in angiogenesis has been suggested by the results of other studies,30,31 whereas soluble E-selectin was shown to induce neovascularization in mouse corneas, as well as induce endothelial migration and tube formation in vitro.32 As demonstrated by the present findings, overexpression of E-selectin is also necessary for circulating EPCs to adhere to a mature endothelial monolayer. To confirm that captured EPCs contribute to neovascularization, we performed in vivo experiments using hind limbs from a murine ischemic model. Our results showed that an administration of E-selectin adenovirus significantly enhanced capillary formation and perfusion, and reduced necrosis caused by ischemia, as compared with control LacZ-transduced mice. Moreover, overexpression of E-selectin alone, although less efficient than combination with EPCs, can potentiate neovascularization in ischemic hind limb model, suggesting that exogenous E-selectin may be able to capture murine endogenous progenitor cells, as shown in Figure 5C.
It is known that a low number of cells obtained from each donor limit the therapeutic application of EPCs, although several approaches have been proposed to overcome this limitation. Injections of granulocyte-macrophage colony-stimulating factor into the peripheral circulation have been reported to cause the migration of EPCs from bone marrow,5 which might be a useful method to collect a large number of EPCs. In addition, the overexpression of vascular endothelial growth factor using gene transfer techniques33 was also demonstrated to be an efficient method for enhancing angiogenesis in vivo.
As compared with those strategies that employed soluble factors, our approach, which used membrane-bound E-selectin, has several advantages, such as site-specific overexpression caused by a local injection of an E-selectin vector, and minimized unnecessary systemic effects. Considering its potential in neovascularization in the absence of exogenous EPCs, overexpression of E-selectin could be a promising approach to potentiate neovascularization.
In conclusion, the present results showed that an administration of E-selectin might be a promising novel technique to efficiently utilize EPCs in therapeutic neovascularization. Further, our data strongly indicate a primary role of E-selectin expressed on activated vascular endothelium for the recruitment of EPCs in vitro and in vivo.
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Acknowledgments |
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We also thank Dr Hideto Ishii for critical review of the manuscript, and Keiko Takahashi and Michiyo Deushi for their technical assistance.
Sources of Funding
This study was supported in part by grant-in-aid for Scientific Research (10178102) and Special Coordination Funds from the Ministry of Education, Science, Technology, and Culture of Japan, and a grant from Ministry of Health, Labor, and Welfare of Japan.
Disclosures
None.
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Footnotes |
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Original received August 13, 2006; final version accepted November 13, 2006.
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