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Richard J Price

Publications and source records attributed to Richard J Price.

17 recordsLinked to original sources
PubMed2026

Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature.

Dysfunctional tumor vessels promote disease progression, whereas improved function enhances therapeutic delivery. However, current approaches to normalize tumor vasculature have limited efficacy. In vascular malformations, vessels are similarly dysfunctional, with endothelial cell (EC) hyperproliferation impairing arterial-venous specification. These defects are corrected with palbociclib, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) that has beneficial effects on tumor and immune cells, but the effects on tumor vasculature are not well characterized. In our studies, murine mammary tumor ECs (TECs) exhibited disrupted cell cycle and specification, and CDK4/6i promoted TEC cycle control, enabling improved tumor vascular function. To investigate transcriptomic changes, we performed single-cell RNA sequencing (scRNAseq) of treated and untreated tumors, and healthy tissues. CDK4/6i-mediated TEC cycle arrest promoted arterial-venous specification, cellular junctions, and pericyte association, and suppressed glycolytic and immunosuppressive gene expression. These effects were associated with increased vessel perfusion, decreased tumor hypoxia, and a more favorable immune landscape with immunotherapy. In scRNAseq datasets from patients treated long-term with CDK4/6i, TECs exhibited similar transcriptomic changes associated with arterial-venous specification, pericyte recruitment, and immune signaling. Thus, in contrast to current strategies, CDK4/6i-mediated vascular changes may be maintained with continued treatment, highlighting the relevance of modulating TEC cycle to improve vessel maturation/function.

Angiogenesis↗
PubMed2006

Targeted therapeutic applications of acoustically active microspheres in the microcirculation.

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.

Animals↗
PubMed2006

Small molecule inducers of angiogenesis for tissue engineering.

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.

Angiogenesis Inducing Agents↗
PubMed2005

Ultrasound-microbubble-induced neovascularization in mouse skeletal muscle.

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.

Animals↗
PubMed2004

Microvascular remodeling and accelerated hyperemia blood flow restoration in arterially occluded skeletal muscle exposed to ultrasonic microbubble destruction.

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.

Animals↗
PubMed2004

Cell proliferation in mesenteric microvascular network remodeling in response to elevated hemodynamic stress.

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.

Actins↗
PubMed2004

Immunohistochemical identification of an extracellular matrix scaffold that microguides capillary sprouting in vivo.

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.

Animals↗
PubMed2003

Spatial and temporal control of angiogenesis and arterialization using focal applications of VEGF164 and Ang-1.

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.

Alginates↗
PubMed2003

Absence of OX-43 antigen expression in invasive capillary sprouts: identification of a capillary sprout-specific endothelial phenotype.

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.

Animals↗
PubMed2003

Enhanced smooth muscle cell coverage of microvessels exposed to increased hemodynamic stresses in vivo.

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.

Actins↗
PubMed2003

Exercise during pregnancy: a practical approach.

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.

Exercise↗
PubMed2002

Stimulation of arteriogenesis in skeletal muscle by microbubble destruction with ultrasound.

BACKGROUND: 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. METHODS AND RESULTS: Pulsed ultrasound (1 MHz) was applied to exposed rat gracilis muscle after intravenous microbubble injection. Capillary rupturing was visually verified by the presence of red blood cells in the muscle, and animals were allowed to recover. Ultrasound-microbubble-treated and contralateral sham-treated muscles were harvested 3, 7, 14, and 28 days later. Arterioles were assessed by smooth muscle alpha-actin staining, and skeletal muscle blood flow was measured with 15- micro m fluorescent microspheres. An approximately 65% increase in arterioles per muscle fiber was noted in treated muscles compared with paired sham-treated control muscles at 7 and 14 days after treatment. This increase in arterioles occurred across all studied diameter ranges at both 7 and 14 days after treatment. Arterioles per muscle fiber in sham-treated and untreated control muscles were comparable, indicating that the surgical intervention itself had no significant effect. Hyperemia nutrient blood flow in treated muscles was increased 57% over that in paired sham-treated control muscles. CONCLUSIONS: Capillary rupturing via microbubble destruction with ultrasound enhances arterioles per muscle fiber, arteriole diameters, and maximum nutrient blood flow in skeletal muscle. This method has the potential to become a clinical tool for stimulating blood flow to organs affected by occlusive vascular disease.

Actins↗
PubMed2002

Influence of injection site, microvascular pressure and ultrasound variables on microbubble-mediated delivery of microspheres to muscle.

OBJECTIVES: 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. BACKGROUND: Microbubbles show promise as targeted drug and gene delivery agents; however, designing optimal microbubble-based therapies will require an understanding of the factors that influence the transport of microbubble-delivered, gene-bearing vehicles to tissue. METHODS: Ultrasound at 1 MHz, with a peak negative pressure amplitude of 0.75 MPa, was applied to microbubbles and 100-nm microspheres in exteriorized rat spinotrapezius muscle. Ultrasound PIs of 1, 3, 5 and 10 s, arterial microsphere injection times of 10 or 40 s and arterial versus venous injection sites were tested. RESULTS: Extravasation point creation and microsphere delivery were greatest when the ultrasound PI was 5 or 10 s. No significant differences in extravasation point creation or microsphere delivery were observed with arterial versus venous microbubble injection, but a trend toward increased microsphere delivery with arterial injection may exist. Decreasing the arterial injection time from 40 to 10 s increased microvascular pressure, which, in turn, substantially enhanced microsphere transport to tissue, without a concomitant increase in the number of extravasation points. CONCLUSIONS: The ultrasound PI and microvascular pressure significantly influence the creation of extravasation points and the transport of microspheres to tissue. These factors may be important in designing and optimizing contrast ultrasound-based therapies.

Animals↗
PubMed2002

Hemodynamic stresses and structural remodeling of anastomosing arteriolar networks: design principles of collateral arterioles.

OBJECTIVE: To investigate the potential influence of hemodynamic stresses on the development of the arcade arteriole (AA) network during normal maturation. METHODS: AA network data were collected from ink-filled Wistar-Kyoto rat gracilis muscles and used to construct hemodynamic computational models of the AA network at 7 (WKY(7)) and 13 (WKY(13)) weeks of age. RESULTS: Mean coefficients of variation for pressure, circumferential wall stress, and wall shear stress were 0.13, 0.12, and 0.48, respectively. Wall shear rate variability across bifurcations generated deviations in mean energy cost that were 9-30% above theoretical minimum, with many bifurcations exhibiting substantially higher energy costs. With the exception of the lowest pressure AA segments, the monotonic relationship between wall shear stress and pressure in the AAs was nearly identical from 7 to 13 weeks of age. CONCLUSIONS: Low coefficients of variation for computed AA pressures indicate that an even pressure head is maintained over the muscle during remodeling of the AA network. The anastomotic structure of the network creates high shear rate variability that, in turn, creates high-energy costs in some regions of the network. The results are consistent with the hypothesis that, during development, the maintenance of mean circumferential wall stress and the pressure-shear stress relationship are operative design principles for collateral arteriole development.

Animals↗
PubMed2002

Contrast ultrasound targeted drug and gene delivery: an update on a new therapeutic modality.

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.

Animals↗