Published online before print April 10, 2008, doi: 10.1161/ATVBAHA.108.165589
© 2008 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Ultrasonic Microbubble Destruction Stimulates Therapeutic Arteriogenesis Via the CD18-Dependent Recruitment of Bone Marrow–Derived Cells
From the Department of Biomedical Engineering (J.C.C., J.S., R.J.P.) and the Cardiovascular Division (A.L.K.), University of Virginia, Charlottesville.
Correspondence to Richard J. Price, PhD, Associate Professor, Department of Biomedical Engineering, University of Virginia, Box 800759, UVA Health System, Charlottesville, VA 22908. E-mail rprice{at}virginia.edu
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Abstract |
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Objective— We have previously shown that, under certain conditions, ultrasonic microbubble destruction creates arteriogenesis and angiogenesis in skeletal muscle. Here, we tested whether this neovascularization response enhances hyperemia in a rat model of arterial insufficiency and is dependent on the recruitment of bone marrow–derived cells (BMDCs) to treated tissues via a β2 integrin (CD18)-dependent mechanism.
Methods and Results— Sprague-Dawley rats, C57BL/6 wild-type mice, and C57BL/6 chimeric mice engrafted with BMDCs from either GFP+ or CD18–/– mice received bilateral femoral artery ligations. Microbubbles (MBs) were intravenously injected, and one gracilis muscle was exposed to pulsed 1 MHz ultrasound (US). Rat hindlimbs exhibited significant increases in adenosine-induced hyperemia and arteriogenesis compared to contralateral controls at 14 and 28 days posttreatment. US-MB–treated wild-type C57BL/6 mice exhibited significant arteriogenesis, angiogenesis, and CD11b+ monocyte recruitment; however, these responses were all completely blocked in CD18–/– chimeric mice. The number of BMDCs increased in US-MB–treated muscles of GFP+ chimeric mice; however, GFP+ BMDCs did not incorporate into microvessels as vascular cells.
Conclusion— In skeletal muscle affected by arterial occlusion, arteriogenesis and hyperemia can be significantly enhanced by ultrasonic MB destruction. This response depends on the recruitment, but not vascular incorporation, of BMDCs via a CD18-dependent mechanism.
Ultrasonic microbubble destruction represents a potential tool in therapeutic strategies, particularly in the targeted stimulation of neovascularization. In the current study, we demonstrate the ability of ultrasound-microbubble interactions to enhance arteriogenesis and perfusion in ischemic tissues through recruitment of marrow-derived cells via CD18. These observations support the development of ultrasound microbubble–based therapies.
Key Words: ultrasonics • contrast media • arteriogenesis • microcirculation • marrow-derived cells
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Introduction |
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Occlusion of the major arteries as a result of atherosclerosis or diabetes often leads to angina, claudication, and the formation of skin ulcers. Although surgical interventions are usually successful, many patients are not amenable to these procedures. For this reason, there is a need to develop new strategies for revascularizing ischemic tissues with minimal surgical invasiveness. To date, promising therapeutic neovascularization methods have been based on the injection or delivery of cytokines,1–3 growth factors,4,5 growth factor genes,6,7 or proangiogenic cells.8–10
Although specifically designed to enhance the contrast in diagnostic ultrasound (US) images,11 microbubbles (MBs) have been studied as potential tools in therapeutic strategies.12 In particular, the use of MBs for targeted drug and gene delivery to large arteries13,14 and tissue6,15,16 has received considerable attention. We have recently explored the use of contrast agent MBs in conjunction with US to stimulate neovascularization. Our studies indicate that, when US-MB interactions are tailored to create capillary poration in skeletal muscle, vascular remodeling17,18 and enhanced hyperemia19 may ensue. Furthermore, this treatment enhances hyperemia in skeletal muscle, particularly in regions of low blood flow, through the formation and lumenal expansion of arterioles spanning low and normal perfusion regions.19 Moreover, we have confirmed that US-MB interactions elicit angiogenic and arteriogenic responses in normal mouse skeletal muscle.18 These results from the rat and mouse motivate the current study in which we test 3 hypotheses. First, using modifications of our previous US-MB treatment protocol in the rat hindlimb model of arterial insufficiency,19 we tested the hypothesis that ultrasonic MB destruction augments not only arteriogenesis, but also total perfusion in regions of limited hyperemia within the gracilis adductor muscle. Second, we tested the hypothesis that arteriogenesis in response to the US-MB treatment requires the recruitment of bone marrow–derived cells (BMDCs)20–22 through the use of chimeric mice in which BMDCs lack CD18 expression. CD18 is the β2 integrin subunit, mediating BMDC firm adhesion to venules during inflammation. Finally, we tested the hypothesis that a short-term (ie, within 24 hours) reduction in perfusion, a therapeutic detriment and possibly an auxiliary long-term (ie, 14 to 28 days) stimulus for neovascularization, is created by US-MB treatment.
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Methods |
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Animal Groups and Hindlimb Models of Arterial Insufficiency
Animal studies were approved by the Animal Care and Use Committee at the University of Virginia and conformed to the American Heart Association Guidelines for the Use of Animals in Research. The Table summarizes the number of animals "n," the experimental procedures, and the timelines for each group. The chimeric mice in Groups V through IX were generated by engrafting host C57BL/6J mice with bone marrow from C57BL/6J, CD18–/–, CD18–/– hypomorph, or GFP+ donor mice as described in the Online Supplement at http://atvb.ahajournals.org. All animals received bilateral femoral artery occlusions (AOs) as shown in the Online Supplement (Figure I).
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Ultrasound-Microbubble Treatment
The gracilis adductor muscle of 1 hindlimb was exposed to ultrasonic MB destruction 14 and 3 days after AO for rats and mice, respectively, as shown in supplemental Figure I using previously described methods.17–19 A shorter experimental duration was used for Groups V through IX because preliminary work had shown robust arteriogenesis in the mouse with this protocol. Therefore, we knew beforehand that short term experiments would be sufficient to identify a potential mechanistic link between CD18 and arteriogenesis. Rats from Groups I through III were reanesthetized by an intraperitoneal (IP) injection of ketamine (80 mgxkg–1) and xylazine (8 mgxkg–1). Gracilis muscles were surgically exposed, US gel was applied, and a 0.75''-diameter 1-MHz unfocused US transducer (Panametrics Inc) was aligned over the muscles (supplemental Figure I). After intravenous (jugular vein) MB injection (0.2 mL at 2.0x109 microbubbles/mL), an US pulse consisting of 100 consecutive 1 MHz sinusoids of 1V peak-to-peak amplitude from a waveform generator (Tektronix AFG-310) and amplified by a 55-dB RF power amplifier (ENI 3100LA), was applied every 5 seconds for 2 minutes. Peak negative pressure was measured as 0.5 MPa with a hydrophone (Specialty Engineering Associates, Model GL-0085), yielding a mechanical index [MI=peak negative pressure/(frequency)1/2] of 0.5. The transducer was then placed over the contralateral muscle without activation to create a paired-sham control muscle. The skin over each muscle was closed with absorbent sutures and the animals recovered. Mice (Groups IV through VIII) were reanesthetized by isoflurane inhalation. Here, a 0.5''-diameter US transducer, yielding an MI of 0.79, and 5x108 MBs/mL were used. Otherwise, all US parameters were identical to those used in the rat, with the exception of the total US application time, which was 4.5 minutes. Procedures for MB formulation are provided in the Online Supplement.
Muscle Blood Flow
At designated time points, gracilis perfusion in Group I animals was assessed using Laser Doppler Perfusion Imaging (LDPI). An established fluosphere method was used to measure absolute resting blood flow (Group I) and adenosine-induced hyperemia (Groups II and III) in gracilis muscles as described in the Online Supplement.
Microvascular Remodeling and Bone Marrow–Derived Cell Recruitment
At the time of tissue harvest, animals from Groups II through IX were reanesthetized. Gracilis muscles were exposed, vasodilated by superfusion with 10–4 mol/L adenosine in Ringer’s solution, perfusion-fixed from an aortic cannula with a pressure of 100 mm Hg, and then dissected free. Whole muscles were incubated in 1:200 Cy3-conjugated monoclonal anti-smooth muscle (SM)-actin overnight (clone 1A4; Sigma), washed, and imaged as whole mounts using confocal microscopy. Whole muscle montages were reconstructed from individual confocal fields-of-view and analyzed to generate arteriolar area density, arteriolar length density, arteriolar and venular diameters, or arteriolar-line intersection metrics as described in the Online Supplement. Arterial vessels were distinguished from venules by SM 
-actin staining intensity and vessel morphology (ie, arterioles—tightly-wrapped SM cells with intense stain versus venules—squamous SM cells with weak stain). Whole muscles from mice in Groups IV through VIII were then cryosectioned. Microvessels were labeled using BS-I lectin, and CD11b staining was used to identify monocytes in Groups IV through VI. Cryosectioned specimens were used to determine SM -actin+ vessels/muscle fiber, BS-I lectin+ vessels/muscle fiber, CD11b+ cells/muscle fiber, and GFP+ cells/muscle fiber, as well as to determine whether GFP+ BMDCs incorporated into microvessels. Detailed procedures are provided in the Online Supplement.
Statistics
Data were analyzed by 2-way repeated measures ANOVA followed by pairwise comparisons with Tukey t tests. Significance was assessed at P<0.05.
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Results |
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Ultrasound-Microbubble Treatment Enhances Arteriogenesis and Flow Capacity in a Rat Hindlimb Model of Arterial Insufficiency
Figure 1A through 1D depict confocal montages of SM
-actin-labeled Group II and III whole mount gracilis muscles. The ratio of SM -actin+ vessel area to total en face muscle area in AO+US+MB muscles was 38% and 31% greater than AO+MB controls at 14 and 28 days posttreatment, respectively (Figure 1E). Vessel intersection analysis of AO+US+MB muscles (Figure 1F) at 14 and 28 days after treatment revealed significant increases of, respectively, 53% and 32% over AO+MB controls. Note that the results from Figure 1E and 1F are derived only from vessels >35 µm in diameter. Preselected first and second order arterioles (A1 and A2) in the AO+US+MB group exhibited maximum diameters that were significantly greater than the diameters of corresponding arterioles in AO+MB controls (Figure 1G). AO+US+MB muscles exhibited significant 39% and 27% increases in adenosine-induced hyperemia when compared to contralateral AO+MB control muscles at 14 and 28 days, respectively (Figure 1H). Throughout Figure 1E through 1H, arteriogenesis and hyperemia in AO+US+MB treated muscles were also consistently greater than nonischemic untreated controls ("No AO"). The "No AO" group in Figure 1H is adapted from Song et al19 and represents the normal adenosine-induced hyperemia level in this muscle after the sham procedure. We have shown that resting flow in nonischemic gracilis muscle is approximately 
5 mL/min/100g.17 Therefore, we estimate that adenosine creates an 8-fold increase in flow over resting conditions in the "No AO" group.
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Ultrasound-Microbubble Treatment Does Not Elicit a Short-Term Reduction in Resting Blood Flow
To determine whether arteriogenesis in response to US-MB treatment could be partly attributable to additional ischemia induced by microbubble bioeffects, we measured perfusion in treated gracilis muscles (Group I) by LDPI at 2 and 24 hours after US-MB treatment (Figure II in the Online Supplement), finding no significant decrease after treatment. These results were confirmed by absolute muscle flows (Figure IIC).
Ultrasound Microbubble–Induced Angiogenesis and Arteriogenesis Are Dependent on the Expression of CD18 by Bone Marrow–Derived Cells
Figure 2A through 2D show SM -actin+ vessels within gracilis muscles from WT and CD18–/– chimeric mice 3 days after US-MB and sham treatment and 6 days after bilateral femoral AOs. Note that the apparent increase in SM -actin+ vessels seen in the AO+US+MB muscles of WT mice does not occur in CD18–/– chimeric mice. Significant increases in arterial vessel length density and in arterial vessel-line intersections per muscle were observed for AO+US+MB muscles from WT, WT chimeric, and GFP+ chimeric mice as compared to AO+MB controls (Figure 2E and 2F). However, in CD18–/– chimeric mice, the US-MB treatment elicited no detectable changes in these arteriogenesis metrics.
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Figure 3A through 3D show SM -actin+ microvessel profiles from AO+US+MB and AO+MB muscle sections of WT and CD18–/– chimeric mice. Consistent with the whole-mount data (Figure 2), SM -actin+ microvessel profiles per muscle fiber was significantly increased in AO+US+MB muscles from WT, WT chimeric, and GFP+ chimeric mice but was unchanged in AO+US+MB treated muscles from CD18–/– chimeric mice (Figure 3E). Grouping these data by diameter revealed that significant increases were only observed in the <10 µm arterioles (Figure III in the Online Supplement).
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Supplemental Figure IVA through IVD illustrate BS-1 lectin+ microvessel profiles from WT and CD18–/– chimeric mice. Here, the number of capillaries per muscle fiber increased with treatment (AO+US+MB) for WT, WT chimeric, and GFP+ chimeric mice in comparison to AO+MB controls; however, CD18–/– chimeras showed no differences between treatment groups (Figure IVE).
Bone Marrow–Derived Cells Are Recruited to Ultrasound Microbubble–Treated Muscles Through CD18 But Do Not Incorporate Into Growing Microvessels
Immunostaining for CD18 in AO+US+MB–treated muscle sections from WT chimeric and CD18–/– chimeric mice was used to verify the effectiveness of the bone marrow engraftment (Online Supplement, Figure V). CD11b-stained muscle sections from AO+US+MB– and AO+MB–treated WT and CD18–/– chimeric mice are shown in Figure 4A through 4D. For WT mice, a 2-fold increase in CD11b+ cells (monocytes) per muscle fiber was observed for AO+US+MB muscles as compared to AO+MB controls (Figure 4E). For WT chimeric mice, the apparent 39% increase in CD11b+ cells per muscle fiber between AO+US+MB and AO+MB was not significant (probability value=0.25). We observed no difference in CD11b+ cell density between AO+US+MB and AO+MB muscles from CD18–/– chimeric mice.
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GFP+ BMDCs were also observed in muscle sections. AO+US+MB muscles showed a significant 2-fold increase in GFP+ cells per fiber over AO+MB controls (supplemental Figure VI). We also scrutinized these sections for the potential incorporation of GFP+ cells into microvessels. We observed 4000 vessel profiles but found no evidence for the transdifferentiation and/or incorporation of GFP+ BMDCs into vascular cells or structures (supplemental Figure VII).
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Discussion |
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Ultrasonic MB destruction enhances vascular remodeling in normal17,18 and ischemic skeletal muscle,19; however, the molecular and cellular mechanisms underlying this phenomenon remain unknown. Here, using a rat model of arterial insufficiency, we demonstrated that ultrasonic microbubble destruction generates angiogenesis, arteriogenesis, and enhanced skeletal muscle hyperemia. Furthermore, through the use of chimeric models in which wild-type mice were engrafted with BMDCs from CD18–/– and GFP+ mice, we found that US-MB–induced vascular remodeling involves the CD18-dependent recruitment, but not vascular incorporation, of BMDCs. Measurements taken shortly after US-MB treatment indicate that the treatment itself does not compromise perfusion in the short-term (supplemental Figure II), thereby excluding the possibility that arteriogenesis occurs in response to additional ischemia. Indeed, a modest vasodilation occurs after ultrasonic MB destruction (supplemental Figure II), raising the possibility that elevated shear and circumferential wall stress could contribute to arteriogenic remodeling including collateral lumen diameter expansion and downstream capillary arterialization.
This study expands on our previous investigations of US-MB–induced arteriogenesis and enhanced hyperemia in the rat.17,19 First, we had previously tested the US-MB method in a model in which 1 of the 2 major feed arteries to the gracilis adductor muscle was occluded and shown that arteriogenesis occurs between regions of low and normal perfusion.19 Here, by using a model in which the femoral artery was occluded upstream of both major gracilis muscle feed arteries, we demonstrated that ultrasonic microbubble destruction may also stimulate arteriogenesis in a muscle entirely affected by arterial occlusion. Second, in that same previous study,19 US-MB treatment was applied concurrently with the placement of arterial ligations. The current study better represents the clinical presentation of vascular disease because we used a 2-week recovery period between arterial occlusion and treatment. It is unlikely that a slowly developing "gradual" femoral artery occlusion would have further enhanced clinical relevance because, after 2 weeks, endogenous changes in angiographic score are essentially the same for acute and gradual occlusions in the rat.23 Finally, by measuring hyperemia throughout the entire muscle, the statistical accuracy of the fluorosphere method was increased over our previous study.19 In the current study, the recommended minimum of 400 fluorospheres per tissue piece was easily achieved.
Our findings (Figure 1H) are supported by a recent study in which increased hindlimb blood flow was observed 4 weeks after ultrasonic microbubble destruction.21 More recently, ultrasonic microbubble destruction was used to deliver vascular endothelial growth factor (VEGF)165 plasmid to ischemic skeletal muscle.6 One experimental group from that study, in which a presumably inert GFP plasmid was delivered by ultrasonic microbubble destruction, is fairly comparable to our US-MB treatment group. Consistent with our results, a significant increase in blood volume, representing enhanced arteriogenesis, was observed6; however, no changes in resting perfusion occurred. Although this result appears to contradict our findings (Figure 1H), note that our measurements were made in the presence of a vasodilator. Thus, it is possible that differences in vascular tone account for this discrepancy. Indeed, in the absence of a vasodilator, we have also seen little to no change in blood flow following ultrasonic microbubble destruction.17
We have previously proposed that ultrasonic microbubble destruction elicits angiogenesis and arteriogenesis by recruiting BMDCs to treated tissue, where they may serve as paracrine growth factor sources or vascular cell precursors.17,19 In support of this hypothesis, other studies have indicated that components of inflammation may be stimulated by ultrasonic MB destruction.24,25 Furthermore, it has been shown that ultrasonic microbubble destruction elicits the recruitment of VEGF+ BMDCs to treated muscle22 and that increasing leukocrit before US-MB treatment enhances arteriogenesis21; however, no "loss of function" studies have been performed to mechanistically prove that blocking BMDC recruitment abrogates US-MB–induced arteriogenesis. To this end, we modified the mouse hindlimb model used in our previous studies18 by adding femoral artery occlusions and using chimeric mice with BMDCs derived from CD18–/– mice. CD18 is the β2 integrin subunit which, along with the L subunit (ie, CD11b), comprises Mac-1, the receptor for intracellular adhesion molecule-1 (ICAM-1). Because ICAM-1/ CD18 interactions mediate firm adhesion during BMDC capture, the deletion of CD18 may be used to abrogate BMDC recruitment. Indeed, we found that, in CD18–/– chimeric mice, CD11b+ monocytes were not recruited to US-MB–treated muscles (Figure 4). Importantly, both arteriogenesis and angiogenesis were also blocked in CD18–/– chimeric mice. Although we anticipated only a moderate reduction of the arteriogenic response in the CD18–/– hypomorph chimera, our measurements showed a surprising decrease in arteriogenesis to the level of the CD18–/– chimera (Figure 2), indicating that even the partial disruption of CD18 abrogates arteriogenesis. Consistent with our results, it has been shown that platelets activated by ultrasonic MB destruction release factors that upregulate endothelial P-selectin and ICAM-1 and an increase in the adhesion of BMDCs.21 Finally, we note that, even though the CD18+ cells that were recruited to ultrasound microbubble–treated muscles were originally derived from bone marrow, it was possible that some CD18+ cell fractions actually resided in nonmarrow compartments, such as the thymus or spleen, immediately before treatment.
Although the CD18–/– chimeric mouse studies demonstrate that BMDC recruitment via CD18 is required for this process, they do not elucidate the role of the recruited BMDCs in angiogenesis and arteriogenesis. Recent studies indicate that, depending on the extent of the stimulus, BMDCs may play important but functionally distinct roles in augmenting vascular remodeling. Although several studies have shown the direct incorporation of bone marrow–derived cells into remodeling vessels,26–29 evidence to the contrary has emerged as well, demonstrating that these cells may not necessarily incorporate into vascular structures30,31 and may serve mainly as paracrine sources of cytokine/growth factor production.32–34 Through the use of GFP+ chimeric mice, we observed the spatial location of BMDCs recruited to US-MB–treated tissues. After observing approximately 4000 microvessels from US-MB treated muscles in GFP+ chimeric mice, we found no evidence for transdifferentiation or direct incorporation of BMDCs into the remodeling vasculature (supplemental Figure VII). When this result is considered in concert with our findings that US-MB treatment fails to stimulate arteriogenesis and angiogenesis in CD18–/– chimeric mice, we conclude that US-MB treatment elicits these responses via the recruitment of CD18+ BMDCs to treated muscle but does not involve the transdifferentiation of BMDCs into vascular cells.
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Acknowledgments |
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Sources of Funding
Dr Price is supported by grants from the National Institutes of Health (R01 HL74082) and the American Heart Association (Grant-in-Aid 0555511U).
Disclosures
Dr Klibanov is a shareholder of Targeson LLC.
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Footnotes |
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Original received September 21, 2007; final version accepted March 27, 2008.
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References |
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