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(Circulation. 2004;109:1647-1652.)
© 2004 American Heart Association, Inc.

Basic Science Reports

CD44 Regulates Arteriogenesis in Mice and Is Differentially Expressed in Patients With Poor and Good Collateralization

N. van Royen, MD, PhD^*; M. Voskuil, MD, PhD^*; I. Hoefer, MD^*; M. Jost, PhD; S. de Graaf, MD; F. Hedwig; J.-P. Andert; T.A.M. Wormhoudt, BS; J. Hua, MD; S. Hartmann, BS; C. Bode, MD; I. Buschmann, MD; W. Schaper, MD, PhD; R. van der Neut, PhD; J.J. Piek, MD, PhD; S.T. Pals, MD, PhD

From the Departments of Cardiology (N.v.R., M.V., S.d.G., J.J.P.) and Pathology (T.A.M.W., R.v.d.N., S.T.P.), Academic Medical Center, University of Amsterdam, the Netherlands; and the Department of Cardiology, University of Freiburg, Freiburg (N.v.R., I.H., M.J., F.H., J.-P.A., J.H., S.H., C.B., I.B.), and Department of Physiology and Experimental Cardiology, Max Planck Institute, Bad Nauheim (W.S.), Germany.

Correspondence to Niels van Royen, MD, PhD, Department of Cardiology, Room B2-114, Academic Medical Center, University of Amsterdam, Meibergdreef 9 1105 AZ, Amsterdam, The Netherlands. E-mail n.vanroyen{at}amc.uva.nl

Received August 22, 2003; revision received November 21, 2003; accepted December 5, 2003.

	Abstract

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Background— Arteriogenesis refers to the development of collateral conductance arteries and is orchestrated by circulating monocytes, which invade growing collateral arteries and act as suppliers of cytokines and growth factors. CD44 glycoproteins are involved in leukocyte extravasation but also in the regulation of growth factor activation, stability, and signaling. Here, we explored the role of CD44 during arteriogenesis.

Methods and Results— CD44 expression increases strongly during collateral artery growth in a murine hind-limb model of arteriogenesis. This CD44 expression is of great functional importance, because arteriogenesis is severely impaired in CD44^–/– mice (wild-type, 54.5±14.9% versus CD44^–/–, 24.1±9.2%, P<0.001). The defective arteriogenesis is accompanied by reduced leukocyte trafficking to sites of collateral artery growth (wild-type, 29±12% versus CD44^–/–, 18±7% CD11b-positive cells/square, P<0.01) and reduced expression of fibroblast growth factor-2 and platelet-derived growth factor-B protein. Finally, in patients with single-vessel coronary artery disease, the maximal expression of CD44 on activated monocytes is reduced in case of impaired collateral artery formation (poor collateralization, 1764±572 versus good collateralization, 2817±1029 AU, P<0.05).

Conclusions— For the first time, the pivotal role of CD44 during arteriogenesis is shown. The expression of CD44 increases during arteriogenesis, and the deficiency of CD44 severely impedes arteriogenesis. Maximal CD44 expression on isolated monocytes is decreased in patients with a poor collateralization compared with patients with a good collateralization.

Key Words: angiogenesis • collateral circulation • glycoproteins • monocytes • growth substances

	Introduction

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Arteriogenesis, the development of a collateral circulation, is a natural escape mechanism to overcome the negative effects of arterial obstruction on tissue perfusion and performance.^1,2 Collateral arteries protect against ischemic damage after myocardial infarction or stroke and alleviate symptoms like angina pectoris and ischemic leg pain.^3,4 However, the innate response to arterial obstruction in patients is very heterogeneous, partly depending on the duration of symptoms and/or the duration of coronary artery disease. To better understand this heterogeneity and to design strategies for the treatment of patients with arterial occlusive disease, the consecutive steps in the process of arteriogenesis need to be elucidated.

CD44 transmembrane glycoproteins are a family of cell-surface receptors expressed on a wide variety of cell types, including leukocytes, endothelial cells, and smooth muscle cells. CD44 serves as a homing receptor for leukocytes,^5–8 by virtue of its ability to bind to hyaluronic acid.⁹ Local invasion of leukocytes, especially monocytes, is a hallmark of collateral artery formation.^10–12 Monocytes/macrophages accumulate around proliferating arteries, where they produce matrix metalloproteinases, proinflammatory cytokines, and growth factors, which orchestrate the remodeling of collateral vessels to high-capacity arteries.^13,14 CD44 also regulates the biological activity of several growth factors, such as fibroblast growth factor (FGF)-2, platelet-derived growth factor (PDGF)-B, and hepatocyte growth factor (HGF). CD44 binds and presents these factors to their high-affinity receptors and promotes signaling and stability by protecting them from degradation.^15–17 In the present study, we therefore explored the role of CD44 during arteriogenesis and provide the first direct evidence for involvement of this receptor in collateral artery formation.

	Methods

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Animals
Specified pathogen–free 8- to 10-week-old CD44-deficient (CD44^–/–) mice on a C57BL/6J background were as described previously.¹⁸ Wild-type (CD44^+/+) C57BL/6J mice were purchased from Iffa Credo, L’Arbresle, France. In all experiments, sex- and age-matched controls were used. A priori approval for the experiments had been obtained from the institutional animal experimentation committee, and experiments were performed according to the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996).

Animal Operation
A total of 37 CD44^–/– male mice and 38 age-matched C57BL/6J wild-type control mice were used for this study. Animals weighed between 25 and 35 g and were 8 to 10 weeks of age. Animals were operated on as previously described.¹⁹

Measurements of Collateral Perfusion in Mice
The development of the collateral circulation was quantified either acutely after ligation (CD44^–/–, n=6; C57BL/6J, n=6), at day 3 (CD44^–/–, n=7; C57BL/6J, n=7) or at day 7 (CD44^–/–, n=9; C57BL/6J, n=8). For this purpose, isolated hind limbs were perfused under maximal vasodilation with fluorescent microspheres. Perfusion ratios of nonligated versus ligated hind limbs were quantified as described.¹⁹

Immunohistochemistry
Tissues were harvested from the proximal hind limb 7 days after femoral artery ligation (CD44^–/–, n=9; C57BL/6J, n=9). For all histological examinations, a total of 5 sections (7 µm thick and with 50-µm distance) per animal were analyzed. Photomicrographs were taken with a fluorescence microscope (DMR, Leica) equipped with a digital camera (DC 300F, Leica). Quantitative analyses were performed in a blinded manner. The following mouse-specific antibodies were used: CD44 (IM7, Pharmingen; 1:200). CD11b to detect infiltrating leukocytes, CD31 (Serotec, 1:200) for quantification of capillaries, FGF-2 (1:200, Santa Cruz Biotechnology), and PDGF-B (1:100, Oncogene Science). Quantification of CD11b-positive perivascular leukocytes (Serotec; 1:150) was performed on high-magnification photomicrographs (x400, 273x273 µm) as previously described.¹² In addition, quantitative analysis was performed on HE-stained sections. Mean arterial wall thickness and vessel diameter were measured for arterial vessels >15 µm using Qfluoro software (Leica). Summed arterial lumen area was calculated from vessel diameters, and total tissue area was measured planimetrically. These parameters were then expressed as a ratio.

Real-Time RT-PCR of Laser-Dissected Collateral Vessels
Cryo-preserved specimens from hind-limb tissue (CD44^–/–, n=6; C57BL/6J, n=6) were cut into serial 5-µm sections. Using a Leica AS LMD laser-dissection microscope, 12 to 20 collateral arteries per animal were harvested and collected in Tris-EDTA buffer solution. Lysis buffer (Qiagen) was added, and samples were incubated at 42°C for 30 minutes. RNA was isolated with Qiagen-Minispin columns, and DNA was digested according to the manufacturer’s instruction (Qiagen).

Reverse transcriptase was performed using PowerScript Reverse Transcriptase (Clontech) with 500 ng of random primer (Promega). Nine microliters of cDNA (1:50 diluted) was transferred into a single well of a 96-well reaction plate (Applied Biosystems) for real-time PCR with the Prism 7700 (Applied Biosystems). SYBR Green PCR Master Mix (11 µL, Applied Biosystems) and 1 µL of each of the gene-specific primer pairs (5 pmol/L) were added.

Primers were designed with Primer3²⁰ to generate products of 80 bp in size and with a melting temperature of 59°C. A typical PCR protocol included a 10-minute denaturation step followed by 50 cycles (95°C denaturation for 1 minute, 60°C annealing, and extension step for 1 minute). Data were analyzed with sequence detection software (ABI PRISM 7700 Version 1.7) according to the user bulletin. Expression levels of target sequences were normalized against ß-actin and expressed as ratios.

Measurement of Collateral Flow Index and Monocytic CD44 Expression in Patients
Fourteen consecutive patients referred to the cardiac catheterization laboratory for a percutaneous transluminal coronary angioplasty (PTCA) of a single coronary lesion (>80% on QCA) were included. Pressures proximal and distal to the stenotic lesion were determined during balloon inflation using a guidewire equipped with a pressure sensor (Wavewire; JOMED). As previously described, collateral flow index (CFI) was then calculated, and patients were divided into a group with poor collateralization and a group with good collateralization according to CFI (cutoff value at 0.25).²¹ In the overall population of patients with coronary artery disease, approximately one third had a CFI value <0.25, indicative of a poor collateralization.²² In addition, patients were scored according to the Rentrop classification,²³ based on automatic contrast injection into the donor artery. Mononuclear cells of patients were isolated over a Ficoll gradient according to standard procedures. Approximately 5x10⁵ cells/mL were incubated with a mouse anti-human CD44 antibody (Hermes 3, 1:1000, PE as a secondary linked fluorescent label) and a FITC-labeled mouse anti-human CD14 antibody (Becton-Dickinson Biosciences; 1:500) for detection of monocytes. By use of FACS analysis (FACSCalibur System; Becton-Dickinson) mean fluorescence intensity for CD44 was measured on CD14-positive monocytes after background subtraction.

Stimulation of isolated monocytes with lipopolysaccharide at different concentrations during the entire protocol did not further increase the expression of CD44 on isolated cells, indicating that the Ficoll isolation and staining procedures already maximally stimulate CD44 expression on CD14-positive monocytes (data not shown).

Statistical Analysis
Results are presented as mean±SD. Significant differences between sample means were determined with an independent-samples t test. Differences with a probability value <0.05 were classified as significant. For correlation between CD44 expression and CFI, linear regression analysis was performed.

	Results

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CD44 Is Strongly Expressed During Arteriogenesis
On femoral artery ligation in wild-type C57BL/6J mice, the expression of CD44 increased strongly in collateral arteries in the quadriceps and adductor muscles of the hind limb (Figure 1, A and B). CD44 was localized on the luminal surface of the endothelial cells (colocalized with CD31) and on the cells constituting the media and on perivascularly accumulated leukocytes (colocalized with CD11b). Expression of CD44 in arteries from the nonligated contralateral limb was very low and limited to the adventitia (Figure 1C). CD44 expression on skeletal muscle of the ligated hind limb was not increased. Capillaries stained positive for CD44 in both the control and the ligated hind limb (Figure 1, D and E). The complete absence of staining in tissues derived from CD44^–/– mice confirmed the specificity of the monoclonal rat anti-mouse CD44 antibody IM7 (Figure 1F).

View larger version (143K): [in this window] [in a new window]   Figure 1. CD44 expression is increased during arteriogenesis. A and B, Strong expression of CD44 on collateral arteries at different stages of maturation. C, In control arteries from nonligated leg, CD44 expression is limited to adventitia. Capillary endothelium in normal hindlimb musculature (D) and in hindlimb musculature from ligated limb (E) expresses CD44. F, Specificity of CD44 antibody is illustrated by total absence of staining in collateral arteries of CD44-null mice. Bars=10 µm.

Arteriogenesis Is Impaired in CD44^–/– Mice
Femoral artery ligation led to a strongly reduced tissue microsphere perfusion directly after the procedure in both wild-type mice and CD44^–/– mice (wild-type, 6.2±2.5% versus CD44^–/–, 8.2±0.9%, P=NS, 100%=perfusion of the nonligated hind limb). The restoration of flow over a period of 7 days was clearly impaired in the CD44^–/– mice compared with the wild-type mice (day 3: wild-type, 14.2±5% versus CD44^–/–, 10.8±2.1%, P=0.06; day 7: wild-type, 54.5±14.9% versus CD44^–/–, 24.1±9.2%, P<0.001; Figure 2A). Consistent with these findings, the mean arterial wall thickness and the ratio of arterial lumen area and tissue area were significantly reduced in the ligated hind-limb musculature of CD44^–/– mice compared with wild-type mice (Figure 2, B and C).

View larger version (13K): [in this window] [in a new window]   Figure 2. Fluorescent microsphere-based perfusion measurements of collateral flow. Flow restores rapidly on femoral artery ligation in wild-type mice over a 7-day period. A, In CD44-null mice, restoration of flow is strongly reduced (wild-type, 54.5±14.9% vs CD44–/–, 24.1±9.2%, P<0.001). B, Wall thickness of collateral arteries is reduced in CD44-null mice compared with wild-type mice 7 days after femoral artery ligation (wild-type, 6.9±2.5 vs CD44–/–, 5.3±1.6 µm, P<0.001). C, Ratio of arterial lumen area and tissue area is lower in ligated hind limb–derived quadriceps muscle of CD44-null mice compared with wild-type mice (control, 0.030±0.016% vs CD44–/–, 0.017±0.009%, P<0.05).

Perivascular Leukocyte Accumulation and Protein Expression of Growth Factors Are Reduced in CD44^–/– Mice
On femoral artery ligation, CD11b-positive leukocytes accumulated around collateral arteries of wild-type mice. Although leukocyte accumulation was also present around arteries in CD44^–/– mice, it was strongly reduced, indicating a role for CD44 in leukocyte trafficking in these CD44^–/– mice under conditions of collateral artery growth (wild-type, 29±12% versus CD44^–/–, 18±7% CD11b-positive cells/square, P<0.01) (Figure 3). Expression of FGF-2 protein in collateral arteries of different sizes was strongly reduced in CD44^–/– mice compared with wild-type animals (Figure 4). Similarly, PDGF-B protein was only weakly expressed in CD44^–/– mice compared with the expression in littermate controls (Figure 5). In control mice, endothelial and smooth muscle cells expressed FGF-2 and PDGF-B protein, whereas perivascular cells and skeletal muscle expressed only minimal amounts of FGF-2 and PDGF-B. Expression of PDGF-B protein in CD44^–/– mice was limited to endothelial cells.

View larger version (72K): [in this window] [in a new window]   Figure 3. Perivascular leukocyte accumulation is reduced in CD44-null mice. A and B, Leukocytes accumulate in perivascular space during arteriogenesis. C and D, Leukocyte accumulation is strongly impaired in CD44-null mice. E, Reduction of perivascular leukocytes as percentage of total cell population (wild-type, 29±12% vs CD44–/–, 18±7% CD11b-positive cells/square, P<0.01). Bars=10 µm (A and C) or 20 µm (B and D).

View larger version (145K): [in this window] [in a new window]   Figure 4. Expression of FGF-2 and PDGF-B protein during arteriogenesis is reduced in CD44-null mice. A and B, At 7 days after femoral artery ligation, developing collateral arteries at different stages of maturation strongly express FGF-2. This expression is limited primarily to vessel wall. C and D, FGF-2 expression is almost undetectable in size-matched collateral arteries derived from CD44-null mice. Bars=10 µm.

View larger version (157K): [in this window] [in a new window]   Figure 5. A and B, Collateral arteries strongly express PDGF-B during arteriogenesis. C and D, PDGF-B is only weakly expressed in CD44-null mice. Bars=10 µm.

In contrast to the decreased protein expression in CD44^–/– mice, we observed no decreased mRNA content for either FGF-2 or PDGF-B (Figure 6). The observed decreased FGF-2 and PDGF-B protein expression in the absence of decreased mRNA expression suggests that the stability of the FGF-2 and PDGF-B proteins is diminished in the absence of CD44.

View larger version (54K): [in this window] [in a new window]   Figure 6. PDGF-B and FGF-2 mRNA expression is increased during arteriogenesis in CD44-null mice. A, Collateral artery (black arrow). B, Vessel is isolated from surrounding tissue by laser microdissection. C, Isolated vessel is stored in buffer solution. D, Between 12 and 20 collateral vessels of each animal are isolated and collected for quantitative RT-PCR analysis. E, mRNA expression ratios for FGF-2 and PDGF-B normalized against values from wild-type mice.

Because a role of CD44 in angiogenesis (ie, capillary sprouting) has been reported, the number of capillaries in the hind-limb muscles of the mice was also compared. We observed no statistically significant difference when comparing capillary counting between CD44^–/– mice and wild-type mice, either in the adductor (wild-type, 6.9±1.8x10² versus CD44^–/–, 6.8±1.9x10² capillaries/mm², P=NS) or in the quadriceps muscle (wild-type, 7.2±2.9x10² versus CD44^–/–, 7.6±3.3x10² capillaries/mm², P=NS).

CD44 Expression on Stimulated Monocytes in Patients With Single-Vessel Coronary Artery Disease
CFI was measured in 14 consecutive patients with single-vessel coronary artery disease. Baseline characteristics are shown in the Table. Seven patients had a CFI 0.25 (mean, 0.21±0.03), and 7 had a CFI >0.25 (mean CFI, 0.41±0.09). No difference was observed in aortic pressure (poor collateralization, 120.0±15.0 versus good collateralization, 120.4±14.0 mm Hg, P=NS). FACS analysis showed a significantly lower CD44 expression on stimulated monocytes from patients with a poor collateralization compared with patients with a good collateralization (poor collateralization, 1764±572 versus good collateralization, 2817±1029 AU, P<0.05) (Figure 7). Comparable results were found when CFI was combined with Rentrop classification (CFI 0.25 and/or Rentrop 1, n=9, 1750±583 AU, versus CFI >0.25 and Rentrop >1, n=5, 3265±725 AU, P<0.01). Linear regression analysis for CD44 expression and CFI on all 14 patients resulted in a correlation coefficient of 0.76 (R²=0.58, P=0.002).

View this table: [in this window] [in a new window]   Baseline Characteristics

View larger version (13K): [in this window] [in a new window]   Figure 7. Patients with poor collateralization as measured by CFI show a reduced maximum CD44 expression on stimulated monocytes compared with patients with good collateralization.

	Discussion

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The present study provides direct evidence for a pivotal role of CD44 in collateral artery development after arterial obstruction. Under physiological conditions, normal endogenous expression of CD44 in the hind-limb musculature is limited to capillaries. In larger arterioles and arteries, expression is minimal and is found only in the adventitia. On femoral artery ligation, we observed a dramatic increase in expression of CD44 in collateral arteries in the quadriceps and adductor muscles. CD44 is expressed strongly on the endothelium, within the vascular wall, and on perivascularly accumulated leukocytes. Most importantly, restoration of flow on femoral artery ligation is severely impaired in CD44^–/– mice. This is accompanied by impaired leukocyte trafficking to perivascular sites of collateral arteries and a reduced protein expression of PDGF-B and FGF-2. Finally, we show that the maximal CD44 expression on stimulated monocytes is reduced in patients with poorly developed collateral arteries.

CD44 is a homing receptor for leukocytes.^5–8 In the present study, we could show that the number of perivascular leukocytes was decreased significantly at sites of collateral artery growth in CD44^–/– mice. The majority of perivascular leukocytes accumulating along developing collateral arteries are monocytes/macrophages, whereas granulocytes are observed only occasionally, suggesting that especially the monocyte/macrophage trafficking is disturbed during arteriogenesis in CD44^–/– mice. Interestingly, defective monocyte trafficking has also been implicated in the strong inhibitory effect of CD44 deficiency on plaque formation in apolipoprotein E–deficient mice crossbred with CD44^–/– mice²⁴ and in the increased sensitivity of CD44^–/– mice to Mycobacterium tuberculosis infection.²⁵

FGF-2 and PDGF-B induce the growth of collateral arteries via direct mitogenic and motogenic effects on endothelial and vascular smooth muscle cells and can act in a synergistic fashion to sustain vessel stability.^14,26 In the present model, FGF-2 and PDGF-B were localized predominantly to the media of collateral vessels, and we observed that their levels were strongly reduced in CD44^–/– mice. Interestingly, these decreased protein levels in CD44^–/– mice were accompanied by increased mRNA levels. Because it has been shown that certain CD44 isoforms can bind growth factors and protect them from proteolysis by extracellular proteinases,^15–17,27 this finding suggests that decreased growth factor stability contributes to the deficient arteriogenic phenotype of CD44^–/– mice.

We recently reported the proarteriogenic effects of TGF-ß₁ in a rabbit hind-limb model.²⁸ Yu and Stamenkovic²⁹ reported that CD44 can facilitate the activation of TGF-ß₁ by localizing matrix metalloproteinase-9 to the plasma membrane. Because the expression of this metalloproteinase is increased during collateral artery growth,¹³ it is possible that the pathway of TGF-ß₁ activation is also disturbed in the present CD44-deficient model. Further studies are needed to test this hypothesis.

It has been shown that CD44 is involved in angiogenesis,^30,31 a process that differs from arteriogenesis in several aspects¹ but shares the feature of endothelial cell proliferation. We found no difference in number of capillaries between CD44^–/– and wild-type mice, indicating that CD44 deficiency does not affect angiogenesis in the present model. However, our model focuses on arteriogenesis rather than angiogenesis, and a model of more severe arterial obstruction, leading to profound tissue ischemia, would be more appropriate to address the role of CD44 in ischemia-induced angiogenesis. Our data from patients with single-vessel coronary artery disease suggest that CD44 is also of importance for the development of a collateral circulation in humans. Further studies are needed to explore whether CD44 fulfills an equally crucial role in clinical arteriogenesis as it does in experimental murine arteriogenesis or whether it serves merely as a marker of the development of collateral growth in patients with coronary artery disease.

Limitations of the Study
Data on protein expression of CD44, FGF-2, and PDGF-B in the mouse hind limb are qualitative data. Preliminary quantitative data from the pig hind limb by use of Western blotting (not shown) also show increased CD44 protein content in proliferating collateral arteries. Further characterization of the interaction of CD44 with different subpopulations of leukocytes and data on long-term effects of CD44 deletion on restoration of perfusion are warranted.

Conclusion
In conclusion, we show for the first time the important role of CD44 during arteriogenesis. CD44 is required both for leukocyte trafficking to the perivascular space of growing collateral arteries and for maintaining the protein expression of FGF-2 and PDGF-B. In patients with single-vessel coronary artery disease, a correlation exists between the degree of development of a collateral circulation and the maximal expression of CD44 by monocytes.

	Footnotes

 
*The first 3 authors contributed equally to this work.

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