Published online before print December 6, 2007, doi: 10.1161/ATVBAHA.107.158741
© 2008 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Human ApoA-I Transfer Attenuates Transplant Arteriosclerosis via Enhanced Incorporation of Bone marrow–derived Endothelial Progenitor Cells
From the Center for Molecular and Vascular Biology (Y.F., F.J., E.V.C., C.B., J.S., B.D.G.), University of Leuven, Belgium; the Center for Transgene Technology and Gene Therapy (M.T.), VIB, University of Leuven, Belgium; and the Department of Cardiology (S.V.L.), Charité, University-Medicine Berlin, Germany.
Correspondence to Bart De Geest, MD, PhD, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. E-mail bart.degeest{at}med.kuleuven.be
Abstract
Objective— Transplant arteriosclerosis is the leading cause of graft failure and death in patients with heart transplantation. Endothelial progenitor cells (EPCs) contribute to endothelial regeneration in allografts. We investigated whether increased HDL cholesterol induced by adenoviral human apoA-I (AdA-I) transfer increases number and function of EPCs, promotes incorporation of EPCs in Balb/c allografts transplanted paratopically in C57BL/6 ApoE–/– mice, and attenuates transplant arteriosclerosis.
Methods and Results— EPC number in ApoE–/– mice was increased after AdA-I transfer as evidenced by 1.5-fold (P<0.01) higher Flk-1 Sca-1–positive cells and 1.4-fold (P<0.01) higher DiI-acLDL isolectin-positive spleen cells. In addition, HDL enhanced EPC function in vitro. Incorporation of bone marrow–derived EPCs was 5.8-fold (P<0.01) higher at day 21 after transplantation in AdA-I-treated apoE–/– mice compared with control mice. Enhanced endothelial regeneration in AdA-I-treated apoE–/– mice as evidenced by a 2.6-fold (P<0.01) increase of CD31-positive endothelial cells resulted in a 1.4-fold (P=0.059) reduction of neointima and a 3.9-fold (P<0.01) increase of luminal area.
Conclusion— Human apoA-I transfer increases the number of circulating EPCs, enhances their incorporation into allografts, promotes endothelial regeneration, and attenuates neointima formation in a murine model of transplant arteriosclerosis.
Endothelial progenitor cells (EPCs) contribute to endothelial regeneration in allografts. Increased HDL cholesterol after human apoA-I transfer in C57BL/6 apoE–/– mice increases EPC number, improves EPC function in vitro, enhances EPC incorporation in allografts, stimulates endothelial regeneration, and attenuates neointima formation in a murine model of transplant arteriosclerosis.
Key Words: high density lipoproteins • apolipoprotein A-I • hypercholesterolemia • endothelial progenitor cells • transplant arteriosclerosis
Plasma levels of high-density lipoprotein (HDL) cholesterol and its major apolipoprotein (apo), apoA-I, are inversely correlated with the incidence of ischemic cardiovascular diseases.1 A meta-analysis of 4 prospective studies indicated that a 1 mg/dL increase of HDL cholesterol is associated with a 2% risk reduction in men and a 3% risk reduction in women.2 Reverse cholesterol transport is considered to be the principal mechanism underlying the beneficial effects of HDL. Additional protective mechanisms include the inhibition of low-density lipoprotein (LDL) oxidation, of cellular adhesion molecule expression, and of platelet activation and aggregation.3 HDL may also contribute to the maintenance of the integrity of the vascular endothelium by stimulating endothelial repair mechanisms.4–6 HDL has been shown to enhance endothelial cell migration in vitro and to promote reendothelialisation in vivo.4 Recent reports have demonstrated that administration of reconstituted HDL increases the recruitment of endothelial progenitor cells (EPCs) into the aortic endothelium of apoE-deficient mice5 and enhances the contribution of bone marrow–derived cells to neovascularization in a mouse hindlimb ischemia model.6
Allograft-accelerated transplantation arteriosclerosis is the leading cause of graft failure and death in patients with heart transplantation.7,8 Hu et al9 have demonstrated that EPCs contribute to endothelial regeneration and to microvessel formation in allografts. Hypercholesterolemia is associated with impaired number and function of EPCs in patients with coronary artery disease10,11 and in apoE-deficient mice.12 Here, we investigated whether increased HDL cholesterol after adenoviral human apoA-I transfer increases number and function of EPCs in hypercholesterolemic apoE–/– mice. Using a paratopic model of transplant arteriosclerosis in apoE–/– mice, we evaluated the hypothesis that human apoA-I transfer may increase number and function of EPCs, enhance incorporation of EPCs in Balb/c allografts, stimulate endothelial repair, and reduce neointima formation. We show that apoA-I transfer increases the circulating number of EPCs, improves EPC function in vitro, enhances EPC incorporation in allografts, stimulates reendothelialization, and attenuates transplant arteriosclerosis.
Materials and Methods
For detailed methodology, please see http://atvb.ahajournals.org. Briefly, 2 weeks after gene transfer or saline injection, a common carotid artery of a female Balb/c donor mouse was transplanted paratopically into recipient C57BL/6 apoE–/– mice in an end-to-side anastomosis on the left common carotid artery as described previously by Shi et al.13 C57BL/6 apoE–/– mice artery transplant recipients were euthanized for histological analysis of the allografts 21 days or 56 days after artery transplantation. To quantify EPC incorporation in allografts, C57BL/6 apoE–/– mice were lethally irradiated with 9.0 Gy at the age of 9 weeks. Transplantation of 6.7x106 bone marrow cells obtained from C57BL/6 apoE–/– β-actin GFP mice was performed 24 hours after irradiation. Gene transfer and artery transplantation were subsequently performed in chimeric mice at the age of 13 and 15 weeks, respectively. Cryosections obtained at day 21 after artery transplantation were incubated with rabbit anti-mouse GFP (Molecular Probes) and rat anti-mouse CD31 (BD) and then labeled with goat anti-rabbit Alexa Fluor 488 and goat anti-rat Alexa Fluor 568 (Molecular Probes) to detect bone marrow–derived endothelial cells.
Results
Human ApoA-I Gene Transfer Induces a Persistent Elevation of HDL Cholesterol in C57BL/6 ApoE–/– Mice
Supplemental Figure IA (please see http://atvb.ahajournals. org) shows human apoA-I plasma levels after transfer with 5x1010 particles of AdA-I in male C57BL/6 apoE–/– mice. AdA-I is an E1E3E4-deleted adenoviral vector14 containing a hepatocyte-specific expression cassette. Human apoA-I expression was sustained for the entire duration of the experiment and was 140±11 mg/dL at day 70 after transfer. Quantification of murine apoA-I levels by Western blot in AdA-I (n=5)-treated mice showed that, compared with baseline levels before gene transfer, murine apoA-I levels were reduced to 34±9.0% at day 14, 16±0.93% at day 35, 21±3.2% at day 56, and 35±7.7% at day 70 after transfer (data not shown). No alteration of murine apoA-I levels was observed after Adnull (n=5) transfer. To evaluate the effect of AdA-I transfer on lipoprotein levels, lipoproteins were fractionated by gel filtration. The lipoprotein profiles at day 0, day 14, day 35, and day 70 after transfer are shown in supplemental Figure IIA and IIB (please see http://atvb.ahajournals.org) for AdA-I and Adnull-treated mice, respectively. Table 1 shows total cholesterol levels, non-HDL cholesterol levels, and HDL cholesterol levels at baseline and at different time points after gene transfer with AdA-I or the control vector Adnull in male C57BL/6 apoE–/– mice (n=10 for each experimental condition). Compared with baseline, AdA-I transfer resulted in a 3.0-fold (P<0.01), 2.5-fold (P<0.01), and 2.2-fold (P<0.01) increase of HDL cholesterol levels at day 14, day 35, and day 70 after transfer, respectively. Non-HDL cholesterol levels were unaltered after AdA-I transfer. Gene transfer with the control vector Adnull did not induce a significant alteration of non-HDL cholesterol levels or HDL cholesterol levels at any time-point (Table 1; supplemental Figure IIB).
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AdA-I Transfer Reduces Oxidative Stress in C57BL/6 ApoE–/– Mice
The concentration of 8-isoprostanes in plasma was determined as a biomarker of oxidative stress. Compared with baseline, the concentration of 8-isoprostanes was 1.6-fold (P<0.05) lower at day 35 (130±18 pg/mL) after AdA-I transfer compared with baseline values (200±24 pg/mL). After transfer with Adnull, the concentration of 8-isoprostanes at day 35 (290±41 pg/mL) was not significantly different compared with baseline (200±32 pg/mL) and 2.2-fold (P<0.01) higher than 35 days after transfer with AdA-I.
Human ApoA-I Gene Transfer Increases the Number of Endothelial Progenitor Cells (EPCs) in the Circulation and in Bone Marrow
The number of Flk-1 Sca-1 double positive cells in the peripheral blood at different time points after AdA-I transfer, Adnull transfer, or saline injection in male C57BL/6 apoE–/– mice is shown in supplemental Figure IB. Because neither Adnull gene transfer (n=5) nor saline injection (n=5) had a significant effect on the number of Flk-1 Sca-1 double positive cells at any time point, the data of both groups were pooled in 1 control group. AdA-I transfer (n=10) resulted in a 1.5-fold increase (P<0.01) of Flk-1 Sca-1 double positive cells at day 10, day 21, and day 35 and a 1.4-fold (P<0.05) increase at day 56 after transfer compared with baseline (supplemental Figure IB). This effect was independent of the presence or absence of an allograft (data not shown). The increase of circulating EPCs was confirmed by quantification of the number of DiI-acLDL fluorescein isothiocyanate (FITC)-isolectin double positive cells after 4 days of ex vivo culture of spleen mononuclear cells isolated at day 10 after transfer. The number of EPCs in the spleen was 1.4-fold (P<0.01) higher after AdA-I transfer (n=6) than after Adnull transfer (n=6) (supplemental Figure IC).
To evaluate whether human apoA-I transfer increases EPC number in bone marrow, bone marrow mononuclear cells were isolated from saline (n=4) and Adnull (n=4) control mice and AdA-I gene transfer mice (n=8) 35 days after injection and cultured for 7 days. The number of DiI-acLDL FITC-isolectin double positive cells per field was 24% (P<0.01) higher in AdA-I treated mice than in control mice (data not shown).
Human ApoA-I Transfer Enhances EPC Function in Hypercholesterolemic ApoE–/– Mice
To investigate the effect of human apoA-I transfer and HDL cholesterol on the function of EPCs, EPC migration, adhesion, and invasion assays were performed. The number of migrated EPCs isolated from Adnull treated mice (n=6) and AdA-I–treated mice (n=6) was increased 1.5-fold (P<0.001) and 1.9-fold (P<0.001), respectively, by addition of 100 µg/mL HDL to the lower chamber (supplemental Figure ID). Migration in the presence of 100 µg/mL HDL in the lower chamber was 1.4-fold (P<0.001) higher for cells isolated from AdA-I–treated mice than for cells isolated from Adnull treated mice (supplemental Figure ID). The number of EPCs isolated from Adnull treated mice (n=5) and AdA-I–treated mice (n=5) that adhered to fibronectin coated plates was increased 1.6-fold (P<0.05) and 2.1-fold (P<0.001), respectively, by addition of 100 µg/mL HDL (supplemental Figure IE). Quantification of the number of EPCs invaded through solidified Matrigel showed that the number of invaded EPCs isolated from Adnull treated mice (n=5) and AdA-I–treated mice (n=5) was increased 1.7-fold (P<0.05) and 2.1-fold (P<0.001), respectively, by addition of 100 µg/mL HDL (supplemental Figure IF). Taken together, these data indicate that HDL improves EPC function in vitro.
Stimulation of EPC Migration and EPC Survival by HDL Is Abrogated in the Presence of Wortmannin
EPCs were isolated from spleens of control C57BL/6 apoE–/– mice. After culture for 7 days, EPC migration was evaluated in the presence of 100 µg/mL bovine serum albumin (control; n=4), HDL (100 µg/mL; n=4), or HDL (100 µg/mL; n=4) plus wortmannin (200 nmol/L). The 1.6-fold (P<0.01) increase of EPC migration in the presence of HDL compared with controls was completely abrogated when wortmannin was added to HDL (supplemental Figure IIIA). These observations were confirmed in experiments using human EPCs isolated from 4 healthy female volunteers and human HDL (supplemental Figure III.B). Taken together, these data suggest that improved EPC function by HDL is dependent on phosphatidylinositol 3-kinase signal transduction.
Under conditions of serum and growth factor deprivation, HDL (100 µg/mL; n=6) increased the number of surviving EPCs 1.6-fold (P<0.001) compared with bovine serum albumin (100 µg/mL; n=6). In the presence of wortmannin (200 nmol/L; n=6), enhanced survival induced by HDL was completely abrogated (supplemental Figure IIIC).
Human ApoA-I Gene Transfer Reduces Intimal Area in Allografts
The common carotid artery of female Balb/c mice (H2d) was transplanted paratopically to male C57BL/6 apoE–/– mice (H2b) 2 weeks after gene transfer or saline injection. Because Adnull transfer did not induce a change of lipoprotein levels (supplemental Figure IIB) nor significant differences in morphometric parameters compared with saline injected mice, morphometric data of saline and Adnull-treated mice were pooled in 1 control group (Table 2). At day 21, the intimal area was 83 000±20 000 µm2 in Adnull treated mice (n=7) and 93 000±13 000 µm2 in saline mice (n=8). At day 56, the intimal area was 87 000±8300 µm2 in Adnull-reated mice (n=13) and 97 000±20 000 µm2 (n=13) in saline-treated mice. Compared with control mice, intimal area was reduced 1.4-fold (P=0.059) and luminal area was increased 3.9-fold (P<0.01) in AdA-I–treated mice at day 21 after transplantation. At day 56 after transplantation, no significant reduction of neointima was observed in AdA-I–treated mice but luminal area was 16-fold (P<0.001) higher compared with control mice (Table 2). The increase in luminal area is explained by more pronounced expansive remodeling because the area within the internal elastical lamina was 1.3-fold (P<0.05) higher at day 56 after artery transplantation in AdA-I–treated mice than in control mice. Representative sections of neointima formation at day 21 and day 56 after transfer in control and AdA-I–treated mice are shown in Figure 1.
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Human ApoA-I Transfer Reduces Allograft Inflammation
Please see http://atvb.ahajournals.org.
Significant loss of endothelial cells in allografts at day 1 and day 3 after transplantation
To evaluate the degree of endothelial denudation after transplantation, the number of CD31-positive endothelial cells was quantified in allografts at day 1 (n=5) and day 3 (n=5) after transplantation in C57BL/6 apoE–/– mice injected 14 days before with 5x1010 particles of Adnull or AdA-I. Compared with the number of CD31-positive endothelial cells in the common carotid artery of nontransplanted Balb/c mice (48±4.5; n=5), the number of CD31-positive endothelial cells in allografts was 3.4-fold (P<0.01) reduced at day 1 after transplantation of mice pretreated with Adnull (14±0.51) or AdA-I (14±1.5). At day 3, the number of CD31-positive endothelial cells was 2.6-fold (P<0.01) and 2.1-fold (P<0.01) lower in allografts of Adnull (18±3.4) and AdA-I (23±2.4)-treated mice, respectively, than in the nontransplanted common carotid artery of Balb/c mice. The degree of endothelial cell loss was not significantly different between AdA-I and Adnull treated mice at day 1 or day 3 after transfer. As an index of the number of CD31-positive endothelial cells per unit of surface lining the arterial lumen, the number of endothelial cells per section was divided by the circumference of the artery lumen in each section. This index was 0.031±0.0030 in the common carotid artery of nontransplanted Balb/c mice, 0.011±0.0013 at day 1 and 0.013±0.0025 at day 3 after transplantation in Adnull pretreated mice, and 0.010±0.0013 at day 1 and 0.015±0.0021 at day 3 after transplantation in AdA-I–treated mice.
Human ApoA-I Transfer Increases Endothelial Regeneration and EPC Incorporation in Allografts
The number of CD31–positive endothelial cells was 2.6-fold (P<0.01) and 13-fold (P<0.0001) higher at day 21 (supplemental Figure IVA) and day 56 (supplemental Figure IVB) after transplantation, respectively, in AdA-I–treated mice compared with control mice. This was confirmed by a significant increase of the number of Tie2-positive endothelial cells at day 56 after transplantation (data not shown). CD31-positive cells were lining the allograft lumen at day 21 after transplantation whereas at day 56, we also observed CD31 positive microvessels within the neointima, particularly in AdA-I–treated mice (supplemental Figure V). At day 21, no microvessels were observed in the neointima. The index of the number of CD31-positive endothelial cells per unit of surface lining the arterial lumen was 1.5-fold (P<0.05) higher at day 21 after transplantation in AdA-I–treated mice (0.027±0.0036) compared with control mice (0.018±0.0024) and not significantly different compared with nontransplanted common carotid arteries of Balb/c mice (0.031±0.0030). To quantify the incorporation of bone marrow–derived EPCs in allografts at day 21 after transplantation, bone marrow transplantation with bone marrow of C57BL/6 apoE–/– β-actin GFP mice was performed 4 weeks before gene transfer or saline injection. Supplemental Figure IVC shows that the number of incorporated CD31 GFP double positive cells was 5.8-fold (P<0.01) higher at day 21 after transplantation in AdA-I–treated chimeric mice (n=10) compared with control chimeric mice (n=10). The ratio of the number of CD31 GFP double positive cells versus the total number of CD31-positive cells increased from 0.064±0.023 in control mice to 0.22±0.040 (P<0.01) in AdA-I–treated mice. Double positive staining for CD31 and GFP is shown in Figure 2.
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Discussion
The main findings of the present study are that (1) increased HDL cholesterol after human apoA-I gene transfer increases the number of endothelial progenitor cells (EPCs) in the circulation and in bone marrow in apoE–/– mice; (2) HDL improves EPC function in vitro; (3) human apoA-I transfer stimulates incorporation of bone marrow–derived EPCs in the regenerating endothelium of allografts and enhances regeneration of the endothelium; (4) neointima formation is attenuated after human apoA-I transfer in this murine model of transplant arteriosclerosis.
The loss of endothelial function and integrity initiates a cascade of events that may lead to native atherosclerosis, vein graft atherosclerosis, restenosis after percutaneous revascularization, and transplant arteriosclerosis.15–18 EPCs have been shown to contribute to reendothelialisation and neovascularization and may play an essential role in endothelial maintenance and repair.9,12,19,20 Hypercholesterolemia is associated with impaired number and function of EPCs in apoE-deficient mice.12 Epidemiological studies show reduced number and function of EPCs in the presence of cardiovascular risk markers such as hypercholesterolemia, hypertension, diabetes, and hyperhomocysteinemia.10,11,21–25 In contrast, a positive correlation between HDL cholesterol plasma levels and circulating EPCs has been observed in cross-sectional studies.26,27 Tso et al5 recently reported that a single administration of reconstituted HDL 18 hours before euthanasia of apoE-deficient mice enhanced the incorporation of Sca-1–positive cells in the thoracic aortic endothelium.5 In another study, injection of reconstituted HDL twice per week was shown to augment collateral development in a murine model of hindlimb ischemia and doubled EPC incorporation in the process of neovascularization.6 Here, we show for the first time that a persistent increase of HDL cholesterol after human apoA-I gene transfer in hypercholesterolemic apoE–/– mice results in a sustained increase of the number of EPCs in the circulation and in bone marrow. HDL enhances EPC function in vitro as evidenced by stimulation of EPC migration, adhesion, and invasion. The enhanced EPC incorporation in the regenerating endothelium of allografts in the current study is in line with the increase of EPC incorporation in the process of neovascularization in the study of Sumi et al.6 The 2.5-fold to 3.0-fold increase of HDL cholesterol in apoE–/– mice after human apoA-I transfer in the current study is similar as in C57BL/6 apoE–/– human apoA-I transgenic mice that were characterized by potent inhibition of progression of native atherosclerosis.28,29
Recently, it was demonstrated that reconstituted HDL stimulates the phosphatidylinositol 3-kinase/Akt signaling pathway to regulate human EPC differentiation.6 Here we show that the stimulation of murine and human EPC migration by HDL is abrogated in the presence of wortmannin, suggesting that the enhancement of EPC function in vitro by HDL is mediated at least in part via a phosphatidylinositol 3-kinase signal transduction pathway. In addition, the current study demonstrates that HDL isolated from AdA-I–treated mice enhances survival of EPCs under conditions of serum and growth factor deprivation. The effect of HDL on EPC survival is inhibited by wortmannin, consistent with phosphatidylinositol 3-kinase/Akt signaling.6 Oxidative stress is likely to be an important mediator of reduced number and function of EPCs in the presence of hypercholesterolemia.30 Human apoA-I transfer resulted in a reduction of oxidative stress as evidenced by a decrease of the concentration of 8-isoprostanes. This may also have contributed to increased number and function of EPCs in apoE–/– mice after human apoA-I transfer.
The impact of bone marrow progenitor cells as a source of endothelial cells has been shown by Hu et al9 who provided evidence that more than 30% of regenerated endothelial cells on the surface of large vessel allografts originated from bone marrow progenitor cells. The data of the current study show that human apoA-I transfer not only increases the absolute number of CD31-positive endothelial cells but also the ratio of the number of CD31 GFP double positive cells versus the total number of CD31 positive cells, indicating an enhanced contribution of bone marrow–derived cells to endothelial regeneration in the allograft at day 21 after transplantation. Therefore, the effect of increased HDL cholesterol on incorporation of EPCs is likely to be critical in promoting reendothelialization.
Myointimal hyperplasia and extracellular matrix accumulation in allografts occur as a consequence of endothelial injury and dysfunction caused by immunologic and nonimmunologic factors.31 Increased HDL cholesterol after human apoA-I transfer may have altered the development of transplant vasculopathy by accelerated regeneration of the endothelium, by reducing inflammation, or by inhibiting vascular smooth muscle migration and proliferation. Whereas effects on inflammation and vascular smooth muscle cells may be partially endothelium independent, accelerated endothelial regeneration after human apoA-I transfer as a result of increased EPC incorporation or effects on local endothelial cells4 likely is a key factor for the observed attenuation of transplant arteriosclerosis at day 21 after transfer. Reduced inflammation after human apoA-I transfer may have contributed to the reduction of transplant arteriosclerosis. HDL is known to inhibit the expression of E- and P-selectin as well as vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule-1 (ICAM-1) stimulated by either cytokines, oxidized LDL, or C-reactive protein.32,33
The striking difference in the number of CD31 endothelial cells at day 56 after human apoA-I transfer partially reflects increased microvessel formation within the neointima. Although we did not evaluate the contribution of EPCs to microvessel formation in the neointima at day 56 after transplantation in the current study, EPCs have previously been shown to contribute to microvessel formation within the neointimal lesions of allografts.9 Antiangiogenic therapy limits experimental atherogenesis of allografts.34 Increased microvessel formation induced by HDL may have promoted neointima formation between day 21 and day 56 after transfer. Neointima formation in this murine model of transplant arteriosclerosis is unopposed by immunosuppressive drugs. A protective intervention can therefore be expected to retard the progression of neointima formation, but not to prevent extension of the neointima to nearly obliteration of the lumen at later time points.
Notwithstanding the absence of an effect of human apoA-I transfer on the extent of neointima formation at day 56 after transplantation, luminal size was significantly increased as a result of more pronounced expansive remodeling. Higher HDL cholesterol levels were also associated with expansive remodeling in the left coronary system in humans.35,36 Whereas expansive remodeling is often associated with increased inflammation,37 expansive remodeling in the current study occurs in the setting of reduced inflammation. Several animal studies have previously shown that flow-induced expansive remodeling does not depend on a local inflammatory response.38–40 Flow-related remodeling depends on the presence of endothelium41 and nitric oxide is an essential intermediate in the shear-induced remodeling response.38–40 We speculate that the increased expansive remodeling of allografts between day 21 and day 56 in AdA-I–treated mice may have been mediated at least in part by accelerated regeneration of the endothelium and by enhanced endothelial NO production induced by HDL.42
In conclusion, human apoA-I transfer increases the number of EPCs in hypercholesterolemic apoE–/– mice, enhances the incorporation of bone marrow–derived EPCs into transplanted arteries in apoE–/– mice, promotes endothelial regeneration, and attenuates neointima formation in a murine model of transplantation arteriosclerosis.
Acknowledgments
We thank V. Carlier for determination of the cytokine profile and J. Hendrix and Z. Zhang for excellent technical assistance.
Sources of Funding
This work was supported by grants G.0563.05 and G.0564.05 of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. The Center for Molecular and Vascular Biology is supported by the Excellentiefinanciering KU Leuven (EF/05/013).
Disclosures
Frank Jacobs is a Research Assistant of the Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen. Eline Van Craeyveld is a Research Assistant of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. Marc Tjwa is a Postdoctoral Fellow of the Instituut voor de Aanmoediging van Innovatie door Wetenschap en Technologie in Vlaanderen.
Footnotes
Original received April 12, 2007; final version accepted November 21, 2007.
References
1. Gordon DJ, Rifkind BM. High-density lipoprotein–the clinical implications of recent studies. N Engl J Med. 1989; 321: 1311–1316.[Medline] [Order article via Infotrieve]
2. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR Jr, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989; 79: 8–15.
3. Shah PK, Kaul S, Nilsson J, Cercek B. Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins: an idea whose time for testing is coming, part I. Circulation. 2001; 104: 2376–2383.
4. Seetharam D, Mineo C, Gormley AK, Gibson LL, Vongpatanasin W, Chambliss KL, Hahner LD, Cummings ML, Kitchens RL, Marcel YL, Rader DJ, Shaul PW. High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I. Circ Res. 2006; 98: 63–72.
5. Tso C, Martinic G, Fan WH, Rogers C, Rye KA, Barter PJ. High-density lipoproteins enhance progenitor-mediated endothelium repair in mice. Arterioscler Thromb Vasc Biol. 2006; 26: 1144–1149.
6. Sumi M, Sata M, Miura SI, Rye KA, Toya N, Kanaoka Y, Yanaga K, Ohki T, Saku K, Nagai R. Reconstituted high-density lipoprotein stimulates differentiation of endothelial progenitor cells and enhances ischemia-induced angiogenesis. Arterioscler Thromb Vasc Biol. 2007.
7. Weis M, von Scheidt W. Cardiac allograft vasculopathy: a review. Circulation. 1997; 96: 2069–2077.
8. Libby P, Pober JS. Chronic rejection. Immunity. 2001; 14: 387–397.[CrossRef][Medline] [Order article via Infotrieve]
9. Hu Y, Davison F, Zhang Z, Xu Q. Endothelial replacement and angiogenesis in arteriosclerotic lesions of allografts are contributed by circulating progenitor cells. Circulation. 2003; 108: 3122–3127.
10. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001; 89: e1–e7.[CrossRef][Medline] [Order article via Infotrieve]
11. Hill JM, Zalos G, Halcox JP, Schenke WH, Waclawiw MA, Quyyumi AA, Finkel T. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003; 348: 593–600.
12. Xu Q, Zhang Z, Davison F, Hu Y. Circulating progenitor cells regenerate endothelium of vein graft atherosclerosis, which is diminished in ApoE-deficient mice. Circ Res. 2003; 93: e76–e86.[CrossRef][Medline] [Order article via Infotrieve]
13. Shi C, Russell ME, Bianchi C, Newell JB, Haber E. Murine model of accelerated transplant arteriosclerosis. Circ Res. 1994; 75: 199–207.
14. Van Linthout S, Lusky M, Collen D, De Geest B. Persistent hepatic expression of human apoA-I after transfer with a helper-virus independent adenoviral vector. Gene Ther. 2002; 9: 1520–1528.[CrossRef][Medline] [Order article via Infotrieve]
15. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999; 340: 115–126.
16. Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med. 2002; 8: 1249–1256.[CrossRef][Medline] [Order article via Infotrieve]
17. Davies MG, Hagen PO. Pathobiology of intimal hyperplasia. Br J Surg. 1994; 81: 1254–1269.[Medline] [Order article via Infotrieve]
18. Mayr M, Li C, Zou Y, Huemer U, Hu Y, Xu Q. Biomechanical stress-induced apoptosis in vein grafts involves p38 mitogen-activated protein kinases. Faseb J. 2000; 14: 261–270.
19. Kong D, Melo LG, Gnecchi M, Zhang L, Mostoslavsky G, Liew CC, Pratt RE, Dzau VJ. Cytokine-induced mobilization of circulating endothelial progenitor cells enhances repair of injured arteries. Circulation. 2004; 110: 2039–2046.
20. Werner N, Junk S, Laufs U, Link A, Walenta K, Bohm M, Nickenig G. Intravenous transfusion of endothelial progenitor cells reduces neointima formation after vascular injury. Circ Res. 2003; 93: e17–e24.[CrossRef][Medline] [Order article via Infotrieve]
21. Loomans CJ, de Koning EJ, Staal FJ, Rookmaaker MB, Verseyden C, de Boer HC, Verhaar MC, Braam B, Rabelink TJ, van Zonneveld AJ. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004; 53: 195–199.
22. Rosenzweig A. Circulating endothelial progenitors–cells as biomarkers. N Engl J Med. 2005; 353: 1055–1057.
23. Schmidt-Lucke C, Rossig L, Fichtlscherer S, Vasa M, Britten M, Kamper U, Dimmeler S, Zeiher AM. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation. 2005; 111: 2981–2987.
24. Tepper OM, Galiano RD, Capla JM, Kalka C, Gagne PJ, Jacobowitz GR, Levine JP, Gurtner GC. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002; 106: 2781–2786.
25. Walter DH, Haendeler J, Reinhold J, Rochwalsky U, Seeger F, Honold J, Hoffmann J, Urbich C, Lehmann R, Arenzana-Seisdesdos F, Aicher A, Heeschen C, Fichtlscherer S, Zeiher AM, Dimmeler S. Impaired CXCR4 signaling contributes to the reduced neovascularization capacity of endothelial progenitor cells from patients with coronary artery disease. Circ Res. 2005; 97: 1142–1151.
26. Pellegatta F, Bragheri M, Grigore L, Raselli S, Maggi FM, Brambilla C, Reduzzi A, Pirillo A, Norata GD, Catapano AL. In vitro isolation of circulating endothelial progenitor cells is related to the high density lipoprotein plasma levels. Int J Mol Med. 2006; 17: 203–208.[Medline] [Order article via Infotrieve]
27. Noor R, Shuaib U, Wang CX, Todd K, Ghani U, Schwindt B, Shuaib A High-density lipoprotein cholesterol regulates endothelial progenitor cells by increasing eNOS and preventing apoptosis. Atherosclerosis. 2007; 192: 92–99.[CrossRef][Medline] [Order article via Infotrieve]
28. Paszty C, Maeda N, Verstuyft J, Rubin EM. Apolipoprotein AI transgene corrects apolipoprotein E deficiency- induced atherosclerosis in mice. J Clin Invest. 1994; 94: 899–903.[Medline] [Order article via Infotrieve]
29. Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E–deficient mouse. Proc Natl Acad Sci U S A. 1994; 91: 9607–9611.
30. Yao EH, Yu Y, Fukuda N. Oxidative stress on progenitor and stem cells in cardiovascular diseases. Curr Pharm Biotechnol. 2006; 7: 101–108.[CrossRef][Medline] [Order article via Infotrieve]
31. Rahmani M, Cruz RP, Granville DJ, McManus BM. Allograft vasculopathy versus atherosclerosis. Circ Res. 2006; 99: 801–815.
32. Calabresi L, Gomaraschi M, Franceschini G. Endothelial protection by high-density lipoproteins: from bench to bedside. Arterioscler Thromb Vasc Biol. 2003; 23: 1724–1731.
33. Wadham C, Albanese N, Roberts J, Wang L, Bagley CJ, Gamble JR, Rye KA, Barter PJ, Vadas MA, Xia P. High-density lipoproteins neutralize C-reactive protein proinflammatory activity. Circulation. 2004; 109: 2116–2122.
34. Nykanen AI, Krebs R, Saaristo A, Turunen P, Alitalo K, Yla-Herttuala S, Koskinen PK, Lemstrom KB. Angiopoietin-1 protects against the development of cardiac allograft arteriosclerosis. Circulation. 2003; 107: 1308–1314.
35. Taylor AJ, Burke AP, Farb A, Yousefi P, Malcom GT, Smialek J, Virmani R. Arterial remodeling in the left coronary system: the role of high-density lipoprotein cholesterol. J Am Coll Cardiol. 1999; 34: 760–767.
36. Yoneyama S, Arakawa K, Yonemura A, Isoda K, Nakamura H, Ohsuzu F. Oxidized low-density lipoprotein and high-density lipoprotein cholesterol modulate coronary arterial remodeling: an intravascular ultrasound study. Clin Cardiol. 2003; 26: 31–35.[Medline] [Order article via Infotrieve]
37. Pasterkamp G, Galis ZS, de Kleijn DP. Expansive arterial remodeling: location, location, location. Arterioscler Thromb Vasc Biol. 2004; 24: 650–657.
38. Tronc F, Wassef M, Esposito B, Henrion D, Glagov S, Tedgui A. Role of NO in flow-induced remodeling of the rabbit common carotid artery. Arterioscler Thromb Vasc Biol. 1996; 16: 1256–1262.
39. Guzman RJ, Abe K, Zarins CK. Flow-induced arterial enlargement is inhibited by suppression of nitric oxide synthase activity in vivo. Surgery. 122: 273–279, 1997; discussion 279–280.
40. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling. J Clin Invest. 1998; 101: 731–736.[Medline] [Order article via Infotrieve]
41. Langille BL, O’Donnell F. Reductions in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science. 1986; 231: 405–407.
42. Mineo C, Shaul PW. HDL stimulation of endothelial nitric oxide synthase: a novel mechanism of HDL action. Trends Cardiovasc Med. 2003; 13: 226–231.[CrossRef][Medline] [Order article via Infotrieve]
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