Influence of Injection Site, Microvascular Pressure and Ultrasound Variables on Microbubble-mediated Delivery of Microspheres to Muscle

Journal of the American College of Cardiology. Feb, 2002  |  Pubmed ID: 11849875

Our objective was to test the hypothesis that the ultrasound pulsing interval (PI), microbubble injection site and microvascular pressure significantly influence the transport of 100-nm microspheres to muscle through extravasation sites created by the destruction of microbubbles with ultrasound.

Hemodynamic Stresses and Structural Remodeling of Anastomosing Arteriolar Networks: Design Principles of Collateral Arterioles

Microcirculation (New York, N.Y. : 1994). Apr, 2002  |  Pubmed ID: 11932778

To investigate the potential influence of hemodynamic stresses on the development of the arcade arteriole (AA) network during normal maturation.

Contrast Ultrasound Targeted Drug and Gene Delivery: an Update on a New Therapeutic Modality

Journal of Cardiovascular Pharmacology and Therapeutics. Jul, 2002  |  Pubmed ID: 12232566

The effective delivery of intravascular drugs and genes to regions of pathology is dependent on a number of factors that are often difficult to control. Foremost is the site-specific delivery of the payload to the region of pathology and the subsequent transport of the payload across the endothelial barrier. Ultrasound contrast agent microbubbles, which are typically used for image enhancement, are capable of amplifying both the targeting and transport of drugs and genes to tissue. Microbubble targeting can be achieved by the intrinsic binding properties of the microbubble shells or through the attachment of site-specific ligands. Once microbubbles have been targeted to the region of interest, microvessel walls can be permeabilized by destroying the microbubbles with low-frequency, high-power ultrasound. A second level of targeting specificity can be achieved by carefully controlling the ultrasound field and limiting microbubble destruction to the region of interest. When microbubbles are destroyed, drugs or genes that are housed within them or bound to their shells can be released to the blood stream and then delivered to tissue by convective forces through the permeabilized microvessels. An alternative strategy is to increase payload volume by coinjecting drug- or gene-bearing vehicles, such as liposomes, with the microbubbles. In this manifestation, microbubbles are used for creating sites of microvessel permeabilization that facilitate drug or gene vehicle transport. Recent work in the emerging field of contrast ultrasound-based therapeutics, with particular emphasis on the delivery of drugs and genes to tissue through microvascular networks is reviewed.

Stimulation of Arteriogenesis in Skeletal Muscle by Microbubble Destruction with Ultrasound

Circulation. Sep, 2002  |  Pubmed ID: 12234963

The application of ultrasound to microbubbles in skeletal muscle creates capillary ruptures. We tested the hypothesis that this bioeffect could be used to stimulate the growth and remodeling of new arterioles via natural repair processes, resulting in an increase in skeletal muscle nutrient blood flow.

Angiogenic Stimulus Determines the Positioning of Pericytes Within Capillary Sprouts in Vivo

Microvascular Research. Jan, 2003  |  Pubmed ID: 12535871

Enhanced Smooth Muscle Cell Coverage of Microvessels Exposed to Increased Hemodynamic Stresses in Vivo

Circulation Research. May, 2003  |  Pubmed ID: 12663481

During vascular remodeling in adult organisms, new capillary growth is often coupled with the adaptation of arterioles and venules, a process that requires the recruitment and differentiation of precursor cells into smooth muscle. We studied the in vivo adaptation of microvessels in the presence of elevated pressure and circumferential wall stress using a ligation strategy for mesenteric microvascular networks. Acute pressure increases of 42.6+/-18% and 17.1+/-2.3% were respectively elicited in the 25- to 30-microm-diameter venules and arterioles supplying the networks. Wall shear rates were not significantly changed; however, diameters were increased in >10-microm-diameter venules and >20-microm-diameter arterioles. Smooth muscle cell contractile phenotype was determined in all microvessels by observing the expression of smooth muscle myosin heavy chain (SM-MHC; a marker of fully differentiated smooth muscle) and smooth muscle alpha-actin (a marker for all smooth muscle, including immature smooth muscle of fibroblast/pericyte lineage). The ratio of SM-MHC positive vessel length to smooth muscle alpha-actin-positive vessel length increased >2-fold after 5 and 10 days of the ligation treatment. Smooth muscle proliferation was studied by bromodeoxyuridine incorporation, and the increase in SM-MHC-labeled microvessel length density was accompanied by no measurable change in proliferation of SM-MHC-labeled cells 5 and 10 days after ligation. These results indicate that after a period of 5 or 10 days, mesenteric microvessels <40 microm in diameter exposed to elevated pressure and wall strain exhibit an enhanced coverage of mature, fully differentiated smooth muscle cells.

Exercise During Pregnancy: a Practical Approach

Current Sports Medicine Reports. Dec, 2003  |  Pubmed ID: 14583162

Attitudes toward exercise during pregnancy have changed dramatically over the past 20 years. Recent studies show that, in most cases, exercise is safe for both the mother and fetus during pregnancy, and support the recommendation to initiate or continue exercise in most pregnancies. This report discusses the rationale behind the changes, and offers educational tools that may be employed to initiate behavioral change. We also propose exercise prescriptions for pregnant women who are sedentary, physically active, and competitive athletes. Armed with this information, the practitioner will be better equipped to counsel patients and incorporate a discussion on physical activity into prenatal visits.

Spatial and Temporal Control of Angiogenesis and Arterialization Using Focal Applications of VEGF164 and Ang-1

American Journal of Physiology. Heart and Circulatory Physiology. Mar, 2004  |  Pubmed ID: 14604856

Microvascular networks undergo patterning changes that determine and reflect functional adaptations during tissue remodeling. Alterations in network architectures are a result of complex and integrated signaling events. To understand how two growth factor signals interact to stimulate angiogenesis and arterialization, we engineered spatially directed microvascular pattern changes in vivo by using combinations of focally delivered exogenous growth factors. We implanted microdelivery beads containing recombinant vascular endothelial growth factor-164 (VEGF(164)) and recombinant angiopoietin-1* (Ang-1*) into the dorsal subcutaneous tissue of fully anesthetized male Fischer 344 rats implanted with backpack window chambers, and we quantified vascular patterning changes by using intravital microscopy, a combination of architectural metrics, and immunohistochemistry. Focal delivery of VEGF(164) caused spatially directed increases in both the total number and the density of vessels with diameters <25 microm 7 days after microbead implantation. Increases were maintained out to 14 days but were reduced to control values by day 21. The addition of Ang-1* on day 7 maintained these increases out to day 21, induced vessel order ratios comparable to control levels, and was accompanied by increases in the length density of smooth muscle alpha-actin-positive vessels. We achieved spatial control of patterning changes in vivo by using multisignal stimulation via focal delivery of exogenous growth factor combinations and conclude that Ang-1* administered subsequent to VEGF(164) stimulation induces vascular growth while maintaining a network pattern consistent with native patterns that persist in the presence of vehicle control stimulation.

Immunohistochemical Identification of an Extracellular Matrix Scaffold That Microguides Capillary Sprouting in Vivo

The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society. Aug, 2004  |  Pubmed ID: 15258182

To gain insight into how a naturally occurring scaffold composed of extracellular matrix (ECM) proteins provides directional guidance for capillary sprouting, we examined angiogenesis in whole-mount specimens of rat mesentery. Angiogenesis was studied in response to normal maturation, the injection of a mast cell degranulating substance (compound 48/80), and mild wounding. Confocal microscopy of specimens immunolabeled for elastin revealed a network of crosslinked elastic fibers with a density of 140.8 +/- 37 mm of fiber/mm(2) tissue. Fiber diameters ranged from 180 to 1400 nm, with a mean value of 710 +/- 330 nm. Capillary sprouts contained CD31- and OX-43-positive endothelial cells as well as desmin-positive pericytes. During normal maturation, leading endothelial cells and pericytes were in contact and aligned with an elastic fiber in approximately 80-90% of all sprouts. In wounding and compound 48/80-treated specimens, in which angiogenesis was markedly increased, leading endothelial cells remained in contact and aligned with elastic fibers in approximately 60-80% of all sprouts. These observations indicate that elastic fibers are used for endothelial and pericyte migration during capillary sprouting in rat mesentery. The composition of this elastic fiber matrix may provide important clues for the development of tissue-engineered scaffolds that support and directionally guide angiogenesis.

Microvascular Remodeling and Accelerated Hyperemia Blood Flow Restoration in Arterially Occluded Skeletal Muscle Exposed to Ultrasonic Microbubble Destruction

American Journal of Physiology. Heart and Circulatory Physiology. Dec, 2004  |  Pubmed ID: 15319212

We showed previously that microbubble destruction with pulsed 1-MHz ultrasound creates a bioeffect that stimulates arteriogenesis and a chronic increase in hyperemia blood flow in normal rat muscle. Here we tested whether ultrasonic microbubble destruction can be used to create a microvascular remodeling response that restores hyperemia blood flow to rat skeletal muscle affected by arterial occlusion. Pulsed ultrasound (1 MHz) was applied to gracilis muscles in which the lateral feed artery was occluded but the medial feed artery was left intact. Control muscles were similarly occluded but did not receive ultrasound, microbubbles, or both. Hyperemia blood flow and number of smooth muscle (SM) alpha-actin-positive vessels, >30-mum arterioles, and capillaries per fiber were determined 7, 14, and 28 days after treatment. In ultrasound-microbubble-treated muscles, lateral region hyperemia blood flow was increased at all time points and restored to normal at day 28. The number of SM alpha-actin vessels per fiber was increased over control in this region at days 7 and 14 but decreased by day 28, when larger-diameter arterioles became more prevalent in the medial region. The number of capillaries per fiber was increased over control only at day 7 in the lateral region and only at days 7 and 14 in the medial region, indicating that the angiogenesis response was transient and likely did not contribute significantly to flow restoration at day 28. We conclude that ultrasonic microbubble destruction can be tailored to stimulate an arteriogenesis response that restores hyperemia blood flow to skeletal muscle in a rat model of arterial occlusion.

Cell Proliferation in Mesenteric Microvascular Network Remodeling in Response to Elevated Hemodynamic Stress

Annals of Biomedical Engineering. Dec, 2004  |  Pubmed ID: 15675679

The objective of this study was to quantify the proliferation of existing vascular and perivascular cells during a specific form of microvascular remodeling characterized by increased coverage by smooth muscle cells (SMCs), in response to increased mechanical stress. Coordinated ligations of artery/vein pairs in the rat mesentery resulted in hemodynamic stress elevations within the targeted microvascular network. BRDU incorporation per unit length of smooth muscle (SM) alpha-actin positive vessel was evaluated following ligation at 2, 5, and 10 days. At 2 days, BRDU incorporation was significantly increased for both sham and ligated treatments, but the ligated response was not elevated over the sham response. After 5 days, proliferation for both groups returned to unstimulated levels. The results indicate that moderate elevations in hemodynamic stress do not cause perivascular cell proliferation along rat mesenteric microvessels, therefore, the increased coverage of differentiated SMCs along the same microvessels does not involve proliferation of vascular or perivascular cells.

Absence of OX-43 Antigen Expression in Invasive Capillary Sprouts: Identification of a Capillary Sprout-specific Endothelial Phenotype

American Journal of Physiology. Heart and Circulatory Physiology. Jan, 2004  |  Pubmed ID: 14512284

Endothelial cells exhibit a number of unique phenotypes, some of which are angiogenesis dependent. To identify a capillary sprout-specific endothelial phenotype, we labeled angiogenic rat mesentery tissue using a microvessel and capillary sprout marker (laminin), selected endothelial cell markers (CD31, tie-2, and BS-I lectin), and the OX-43 monoclonal antibody, which recognizes a 90-kDa membrane glycoprotein of unknown function. In tissues that were stimulated through wound healing and compound 48/80 application, double-immunolabeling experiments with an anti-laminin antibody revealed that the OX-43 antigen was expressed strongly in all microvessels. However, the OX-43 antigen was completely absent from a large percentage (>85%) of the capillary sprouts that were invading the avascular tissue space. In contrast, sprouts that were introverting back into the previously vascularized tissue retained high levels of OX-43 antigen expression. Double-labeling experiments with endothelial markers indicated that the OX-43 antigen was expressed by microvessel endothelium but was absent from virtually all invasive capillary sprout endothelial cells. We conclude that the absence of OX-43 antigen expression marks a novel, capillary sprout-specific, endothelial cell phenotype. Endothelial cells of this phenotype are particularly abundant in capillary sprouts that invade avascular tissue during angiogenesis.

Surgical Cricothyroidotomy Technique

Anesthesiology. Sep, 2005  |  Pubmed ID: 16129998

Ultrasound-microbubble-induced Neovascularization in Mouse Skeletal Muscle

Ultrasound in Medicine & Biology. Oct, 2005  |  Pubmed ID: 16223645

Ultrasound-microbubble (US-MB) interactions stimulate neovascularization in rat gracilis muscle (GM). We examined microvascular remodeling (MVR) in GMs of C57BL/6 and balb/C mice following ultrasonic MB destruction. A range of MB dosages were administered IV, and exposed GMs received US. Muscles harvested 3, 7 and 14 d posttreatment were stained for vascular markers and assessed for changes in microvessel number, diameter and length. Muscles receiving a low MB dose (LMBD) and US showed significant increases in microvascular density after 3 d, returning to sham levels after one week. A MB dose producing maximum capillary disruptions was then established. This high MB dose (HMBD) facilitated significant MVR in C57BL/6 mice after one week. Balb/C GMs exhibited neovascularization 3 d, but not 7 or 14 d, following US-HMBD treatment. We conclude that HMBD in C57BL/6 mice induces a more sustained neovascularization response compared to balb/C or LMBD-treated C57BL/6 muscles; however, this response is still impermanent.

Targeted Therapeutic Applications of Acoustically Active Microspheres in the Microcirculation

Microcirculation (New York, N.Y. : 1994). Jan, 2006  |  Pubmed ID: 16393947

The targeted delivery of intravascular drugs and genes across the endothelial barrier with only minimal side effects remains a significant obstacle in establishing effective therapies for many pathological conditions. Recent investigations have shown that contrast agent microbubbles, which are typically used for image enhancement in diagnostic ultrasound, may also be promising tools in emergent, ultrasound-based therapies. Explorations of the bioeffects generated by ultrasound-microbubble interactions indicate that these phenomena may be exploited for clinical utility such as in the targeted revascularization of flow-deficient tissues. Moreover, development of this treatment modality may also include using ultrasound-microbubble interactions to deliver therapeutic material to tissues, and reporter genes and therapeutic agents have been successfully transferred from the microcirculation to tissue in various animal models of normal and pathological function. This article reviews the recent studies aimed at using interactions between ultrasound and contrast agent microbubbles in the microcirculation for therapeutic purposes. Furthermore, the authors present investigations involving microspheres that are of a different design compared to current microbubble contrast agents, yet are acoustically active and demonstrate potential as tools for targeted delivery. Future directions necessary to address current challenges and advance these techniques to clinical practicality are also discussed.

Small Molecule Inducers of Angiogenesis for Tissue Engineering

Tissue Engineering. Jul, 2006  |  Pubmed ID: 16889520

Engineering of implantable tissues requires rapid induction of angiogenesis to meet the significant oxygen and nutrient demands of cells during tissue repair. To this end, our laboratories have utilized medicinal chemistry to synthesize non-peptide-based inducers of angiogenesis to aid tissue engineering. In this study, we describe the evaluation of SC-3-149, a small molecule compound with proliferative effects on vascular endothelial cells. Specifically, exogenous exposure of SC-3-149 induced an 18-fold increase in proliferation of human microvascular endothelial cells in vitro at low micromolar potency by day 14 in culture. Moreover, SC-3-149 significantly increased the formation of endothelial cord and tubelike structures in vitro, and improved endothelial scratch wound healing within 24 h. SC-3-149 also significantly inhibited vascular endothelial cell death owing to serum deprivation and high acidity (pH 6). Concurrent incubation of SC-3-149 with vascular endothelial growth factor increased cell survivability under serum-deprived conditions by an additional 7%. In addition, in vivo injection of SC-3-149 into the rat mesentery produced qualitative increases in microvessel length density. Taken together, our studies suggest that SC-3-149 and its analogs may serve as promising new angiogenic agents for targeted drug delivery and therapeutic angiogenesis in tissue engineering.

The Findings of the International Conference on Medical Emergency Teams Are Biased and Misleading

Critical Care Medicine. Mar, 2007  |  Pubmed ID: 17421116

Computational Network Model Prediction of Hemodynamic Alterations Due to Arteriolar Remodeling in Interval Sprint Trained Skeletal Muscle

Microcirculation (New York, N.Y. : 1994). Apr-May, 2007  |  Pubmed ID: 17454671

Exercise training is known to enhance skeletal muscle blood flow capacity, with high-intensity interval sprint training (IST) primarily affecting muscles with a high proportion of fast twitch glycolytic fibers. The objective of this study was to determine the relative contributions of new arteriole formation and lumenal arteriolar remodeling to enhanced flow capacity and the impact of these adaptations on local microvascular hemodynamics deep within the muscle.

Ultrasonic Microbubble Destruction Stimulates Therapeutic Arteriogenesis Via the CD18-dependent Recruitment of Bone Marrow-derived Cells

Arteriosclerosis, Thrombosis, and Vascular Biology. Jun, 2008  |  Pubmed ID: 18403725

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 beta2 integrin (CD18)-dependent mechanism.

Acoustic Attenuation by Contrast Agent Microbubbles in Superficial Tissue Markedly Diminishes Petechiae Bioeffects in Deep Tissue

Investigative Radiology. May, 2008  |  Pubmed ID: 18424953

To measure how ultrasound attenuation by contrast agent microbubbles (MBs) in superficial tissue affects petechiae creation in underlying deep tissue.

Targeted Delivery of Nanoparticles Bearing Fibroblast Growth Factor-2 by Ultrasonic Microbubble Destruction for Therapeutic Arteriogenesis

Small (Weinheim an Der Bergstrasse, Germany). Oct, 2008  |  Pubmed ID: 18720443

Therapeutic strategies in which recombinant growth factors are injected to stimulate arteriogenesis in patients suffering from occlusive vascular disease stand to benefit from improved targeting, less invasiveness, better growth-factor stability, and more sustained growth-factor release. A microbubble contrast-agent-based system facilitates nanoparticle deposition in tissues that are targeted by 1-MHz ultrasound. This system can then be used to deliver poly(D,L-lactic-co-glycolic acid) nanoparticles containing fibroblast growth factor-2 to mouse adductor muscles in a model of hind-limb arterial insufficiency. Two weeks after treatment, significant increases in both the caliber and total number of collateral arterioles are observed, indicating that the delivery of nanoparticles bearing fibroblast growth factor-2 by ultrasonic microbubble destruction may represent an effective and minimally invasive strategy for the targeted stimulation of therapeutic arteriogenesis.

Capillary Sprout Endothelial Cells Exhibit a CD36 Low Phenotype: Regulation by Shear Stress and Vascular Endothelial Growth Factor-induced Mechanism for Attenuating Anti-proliferative Thrombospondin-1 Signaling

The American Journal of Pathology. Oct, 2008  |  Pubmed ID: 18772338

Endothelial cells acquire distinctive molecular signatures in their transformation to an angiogenic phenotype that are indicative of changes in cell behavior and function. Using a rat mesentery model of inflammation-induced angiogenesis and a panel of known endothelial markers (CD31, VE-cadherin, BS-I lectin), we identified a capillary sprout-specific endothelial phenotype that is characterized by the marked down-regulation of CD36, a receptor for the anti-angiogenic molecule thrombospondin-1 (TSP-1). TSP-1/CD36 interactions were shown to regulate angiogenesis in this model as application of TSP-1 inhibited angiogenesis and blockade of both TSP-1 and CD36 accelerated angiogenesis. Vascular endothelial growth factor, which was up-regulated in the in vivo model, elicited a dose- and time-dependent down-regulation of CD36 (ie, to a CD36 low phenotype) in cultured human umbilical vein endothelial cells. Human umbilical vein endothelial cells that had been conditioned to a CD36 low phenotype with VEGF were found to be refractory to anti-proliferative TSP-1 signaling via a CD36-dependent mechanism. The loss of exposure to wall shear stress, which occurs in vivo when previously quiescent cells begin to sprout, also generated a CD36 low phenotype. Ultimately, our results identified the regulation of endothelial cell CD36 expression as a novel mechanism through which VEGF stimulates and sustains capillary sprouting in the presence of TSP-1. Additionally, CD36 was shown to function as a potential molecular linkage through which wall shear stress may regulate both microvessel sprouting and quiescence.

Expansion of Microvascular Networks in Vivo by Phthalimide Neovascular Factor 1 (PNF1)

Biomaterials. Dec, 2008  |  Pubmed ID: 18804278

Phthalimide neovascular factor (PNF1, formerly SC-3-149) is a potent stimulator of proangiogenic signaling pathways in endothelial cells. In this study, we evaluated the in vivo effects of sustained PNF1 release to promote ingrowth and expansion of microvascular networks surrounding biomaterial implants. The dorsal skinfold window chamber was used to evaluate the structural remodeling response of the local microvasculature. PNF1 was released from poly(lactic-co-glycolic acid) (PLAGA) films, and a transport model was utilized to predict PNF1 penetration into the surrounding tissue. PNF1 significantly expanded microvascular networks within a 2mm radius from implants after 3 and 7 days by increasing microvessel length density and lumenal diameter of local arterioles and venules. Staining of histological sections with CD11b showed enhanced recruitment of circulating white blood cells, including monocytes, which are critical for the process of vessel enlargement through arteriogenesis. As PNF1 has been shown to modulate MT1-MMP, a facilitator of CCL2 dependent leukocyte transmigration, aspects of window chamber experiments were repeated in CCR2(-/-) (CCL2 receptor) mouse chimeras to more fully explore the critical nature of monocyte recruitment on the therapeutic benefits of PNF1 function in vivo.

Influence of Poly(D,L-lactic-co-glycolic Acid) Microsphere Degradation on Arteriolar Remodeling in the Mouse Dorsal Skinfold Window Chamber

Journal of Biomedical Materials Research. Part A. Nov, 2009  |  Pubmed ID: 18980190

Poly(D,L-lactic-co-glycolic acid) (PLGA) is a biodegradable polymer that is widely used for drug delivery. However, the degradation of PLGA alters the local microenvironment and may influence tissue structure and/or function. Here, we studied whether PLGA degradation affects the structure of the arteriolar microcirculation through arteriogenic expansion of maximum lumenal diameters and/or the formation of new smooth muscle-coated vessels. Single microspheres comprised of 50:50 PLGA (521 +/- 52.7 microm diameter), 50:50 PLGA with bovine serum albumin (BSA) (547 +/- 62.2 microm), 85:15 PLGA (474 +/- 52.6 microm), or 85:15 PLGA with BSA (469 +/- 57.2 microm) were implanted into mouse dorsal skinfold window chambers, and longitudinal arteriolar diameter measurements were made in the presence of a vasodilator (10(-4)M adenosine) over 7 days. At the end of the 7-day period, the length density of all smooth muscle-coated microvessels was also determined. Implantation of the window chamber alone elicited a 22% increase in maximum arteriolar diameter. However, the addition of 85:15 and 50:50 PLGA microspheres, bearing either BSA or no protein, elicited a significant enhancement of this arteriogenic response, with final maximum arteriolar diameters ranging from 36 to 46% more than their original size. Interestingly, the influence of PLGA degradation on microvascular structure was limited to lumenal arteriolar expansion, as we observed no significant differences in length density of smooth muscle-coated microvessels. We conclude that the degradation of PLGA microspheres may elicit an arteriogenic response in subcutaneous tissue in the dorsal skinfold window chamber; however, it has no apparent effect on the total length of smooth muscle-coated microvasculature.

Bone Marrow-derived Cell-specific Chemokine (C-C Motif) Receptor-2 Expression is Required for Arteriolar Remodeling

Arteriosclerosis, Thrombosis, and Vascular Biology. Nov, 2009  |  Pubmed ID: 19734197

Bone marrow-derived cells (BMCs) and inflammatory chemokine receptors regulate arteriogenesis and angiogenesis. Here, we tested whether arteriolar remodeling in response to an inflammatory stimulus is dependent on BMC-specific chemokine (C-C motif) receptor 2 (CCR2) expression and whether this response involves BMC transdifferentiation into smooth muscle.

Capillary Arterialization Requires the Bone-marrow-derived Cell (BMC)-specific Expression of Chemokine (C-C Motif) Receptor-2, but BMCs Do Not Transdifferentiate into Microvascular Smooth Muscle

Angiogenesis. 2009  |  Pubmed ID: 19777360

Chemokine (C-C motif) receptor-2 (CCR2) regulates arteriogenesis and angiogenesis, facilitating the MCP-1-dependent recruitment of growth factor-secreting bone marrow-derived cells (BMCs). Here, we tested the hypothesis that the BMC-specific expression of CCR2 is also required for new arteriole formation via capillary arterialization. Following non-ischemic saphenous artery occlusion, we measured the following in gracilis muscles: monocyte chemotactic protein-1 (MCP-1) in wild-type (WT) C57Bl/6J mice by ELISA, and capillary arterialization in WT-WT and CCR2(-/-)-WT (donor-host) bone marrow chimeric mice, as well as BMC transdifferentiation in EGFP(+)-WT mice, by smooth muscle (SM) alpha-actin immunochemistry. MCP-1 levels were significantly elevated 1 day after occlusion in WT mice. In WT-WT mice at day 7, compared to sham controls, arterial occlusion induced a 34% increase in arteriole length density, a 46% increase in SM alpha-actin(+) vessels, and a 45% increase in the fraction of vessels coated with SM alpha-actin, indicating significant capillary arterialization. However, in CCR2(-/-)-WT mice, no differences were observed between arterial occlusion and sham surgery. In EGFP(+)-WT mice, EGFP and SM alpha-actin never colocalized. We conclude that BMC-specific CCR2 expression is required for skeletal muscle capillary arterialization following arterial occlusion; however, BMCs do not transdifferentiate into smooth muscle.

Spatial and Temporal Coordination of Bone Marrow-derived Cell Activity During Arteriogenesis: Regulation of the Endogenous Response and Therapeutic Implications

Microcirculation (New York, N.Y. : 1994). Nov, 2010  |  Pubmed ID: 21044213

Arterial occlusive disease is the leading cause of morbidity and mortality throughout the developed world, which creates a significant need for effective therapies to halt disease progression. Despite success of animal and small-scale human therapeutic arteriogenesis studies, this promising concept for treating arterial occlusive disease has yielded largely disappointing results in large-scale clinical trials. One reason for this lack of successful translation is that endogenous arteriogenesis is highly dependent on a poorly understood sequence of events and interactions between bone marrow derived cells (BMCs) and vascular cells, which makes designing effective therapies difficult. We contend that the process follows a complex, ordered sequence of events with multiple, specific BMC populations recruited at specific times and locations. Here, we present the evidence suggesting roles for multiple BMC populations-from neutrophils and mast cells to progenitor cells-and propose how and where these cell populations fit within the sequence of events during arteriogenesis. Disruptions in these various BMC populations can impair the arteriogenesis process in patterns that characterize specific patient populations. We propose that an improved understanding of how arteriogenesis functions as a system can reveal individual BMC populations and functions that can be targeted for overcoming particular impairments in collateral vessel development.

Inhibition of Glioma Growth by Microbubble Activation in a Subcutaneous Model Using Low Duty Cycle Ultrasound Without Significant Heating

Journal of Neurosurgery. Jun, 2011  |  Pubmed ID: 21214331

In this study, the authors sought determine whether microbubble (MB) destruction with pulsed low duty cycle ultrasound can be used to reduce brain tumor perfusion and growth through nonthermal microvascular ablation.

Covalently Linking Poly(lactic-co-glycolic Acid) Nanoparticles to Microbubbles Before Intravenous Injection Improves Their Ultrasound-targeted Delivery to Skeletal Muscle

Small (Weinheim an Der Bergstrasse, Germany). May, 2011  |  Pubmed ID: 21456081

Intravenously injected nanoparticles can be delivered to skeletal muscle through capillary pores created by the activation of microbubbles with ultrasound; however, strategies that utilize coinjections of free microbubbles and nanoparticles are limited by nanoparticle dilution in the bloodstream. Here, improvement in the delivery of fluorescently labeled ≈150 nm poly(lactic-co-glycolic acid) nanoparticles to skeletal muscle is attempted by covalently linking them to albumin-shelled microbubbles in a composite agent formulation. Studies are performed using an experimental model of peripheral arterial disease, wherein the right and left femoral arteries of BalbC mice are surgically ligated. Four days after arterial ligation, composite agents, coinjected microbubbles and nanoparticles, or nanoparticles alone are administered intravenously and 1 MHz pulsed ultrasound was applied to the left hindlimb. Nanoparticle delivery was assessed at 0, 1, 4, and 24 h post-treatment by fluorescence-mediated tomography. Within the coinjection group, both microbubbles and ultrasound are found to be required for nanoparticle delivery to skeletal muscle. Within the composite agent group, nanoparticle delivery is found to be enhanced 8- to 18-fold over 'no ultrasound' controls, depending on the time of measurement. A maximum of 7.2% of the initial nanoparticle dose per gram of tissue was delivered at 1 hr in the composite agent group, which was significantly greater than in the coinjection group (3.6%). It is concluded that covalently linking 150 nm-diameter poly(lactic-co-glycolic acid) nanoparticles to microbubbles before intravenous injection does improve their delivery to skeletal muscle.