Treatment of Ischemic Limbs Based on Local Recruitment of Vascular Endothelial Growth Factor-Producing Inflammatory Cells With Ultrasonic Microbubble Destruction

Yoshida, Junji; Ohmori, Koji; Takeuchi, Hiroto; Shinomiya, Kaori; Namba, Tsunetatsu; Kondô, Isao; Kiyomoto, Hideyasu; Kohno, Masakazu

doi:10.1016/j.jacc.2005.05.052

Cited by 51 publications

(39 citation statements)

References 27 publications

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“…22,23 Postulated mechanisms for this biologic effect have included the recruitment of inflammatory cells, platelets, or bone marrow stem cells, 23 the release of platelet-derived proinflammatory factors which may attract circulating endothelial progenitor cells, 24 or the via the recruitment of VEGF-producing inflammatory cells. 25 Unlike these studies, we found that control microbubble destruction did not result in increases in total or capillary blood flow, and are in keeping with other studies of ultrasound-mediated gene delivery. 12,13 Differences in ultrasound transmit frequency and acoustic power, microbubble composition and doses, methods of blood flow determination, and vessel density measurements between studies could have accounted for these differences.…”

Section: Discussionsupporting

confidence: 90%

Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF ₁₆₅ Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle

Leong‐Poi

Kuliszewski

Lekas

et al. 2007

Circulation Research

152

138

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Abstract-Current methods of gene delivery for therapeutic angiogenesis are invasive, requiring either intraarterial or intramuscular administration. A noninvasive method of gene delivery has been developed using ultrasound-mediated destruction of intravenously administered DNA-bearing carrier microbubbles during their microcirculatory transit. Here we show that chronic ischemia could be markedly improved by ultrasound-mediated destruction of microbubbles bearing vascular endothelial growth factor-165 (VEGF 165 ) plasmid DNA. Using a model of severe chronic hindlimb ischemia in rats, we demonstrated that ultrasound mediated VEGF 165 /green fluorescent protein (GFP) plasmid delivery resulted in a significant improvement in microvascular blood flow by contrast-enhanced ultrasound, and an increased vessel density by fluorescent microangiography, with minimal changes in control groups. The improvement in tissue perfusion was attributed predominantly to increases in noncapillary blood volume or arteriogenesis, with perfusion peaking at 14 days after delivery, followed by a partial regression of neovascularization at 6 weeks. Transfection was localized predominantly to the vascular endothelium of arterioles in treated ischemic muscle. RT-PCR confirmed the presence of VEGF 165 /GFP mRNA within treated ischemic muscle, being highest at day 3 postdelivery, and subsequently decreasing, becoming almost undetectable by 6 weeks. We found a modulation of endogenous growth factor expression in VEGF-treated ischemic muscle, consistent with a biologic effect of ultrasound mediated gene delivery. The results of our study demonstrate the utility of ultrasonic destruction of plasmid-bearing microbubbles to induce therapeutic arteriogenesis in the setting of severe chronic ischemia.

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Section: Discussionsupporting

confidence: 90%

Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF ₁₆₅ Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle

Leong‐Poi

Kuliszewski

Lekas

et al. 2007

Circulation Research

152

138

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“…Currently it is believed that inhibition of hTLR4 or hTLR4 related downstream activity can subsequently attenuate plaque formation or even plaque rupture [35,36]. Of note, formation of collateralarteriogenesis which is an important mechanism to increase blood flow to ischemic parts [37,38] is mediated by inflammatory cytokines [39,40]. The beneficial effects of hTLR4 in arteriogenesis were seen by Grote study [41].…”

Section: Discussionmentioning

confidence: 96%

Association of monoctye expression of Toll-like receptor 4 and its related cytokines with coronary luminal stenosis

Bagheri¹,

Sohrabi²,

Movassaghpur³

et al. 2013

ABB

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Toll-like receptors are well-defined barriers in innate immunity. Among them hTLR4 on the surface of monocytes, plays a critical role in the formation of atherosclerotic plaques, plaque instability and arterial remodeling through production of inflammatory cytokines. This study was designed to examine the association of hTLR4 monocyte expression and response with the severity of coronary stenosis in patients with stable angina (SA). Blood samples were obtained from 39 patients with SA who were scheduled for a coronary angiography and from 28 healthy volunteers. The samples were collected before the procedure. Expression of hTLR4 on CD14 + monocytes and serum levels of TNF-α and IL-1β were measured using flowcytometry and ELISA techniques respectively. Percentage stenosis diameter was measured by comparing the area of coronary stenosis to an adjacent normal segment of the vessel. Compared with control group, patients showed upregulation of hTLR4 + /CD14 + monocytes. Furthermore, patients with more severe coronary stenosis exhibited enhanced expression of hTLR4 + /CD14 + monocytes (p < 0.01). This was paralleled by elevation in the serum levels of TNF-α (p < 0.05) and IL-1β. In addition, significant correlations were seen between percentage stenosis diameter and monocyte expression of hTLR4 as well as TNF-α. hTLR4 monocytic expression and related cytokines are positively associated percentage stenosis diameter. These results suggest that hTLR4 activity may be involved in progression of atherosclerosis.

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“…This test has been used in the functional evaluation of arteriogenesis and angiogenesis in animals following induction of hind limb ischemia, and improved vessel formation was found to correlate with time to exhaustion [15][16][17][18]. Time to exhaustion was defined as a characteristic change in gait.…”

Section: Functional Assay: Treadmillmentioning

confidence: 99%

Impaired recovery of hind limb muscle perfusion following ischemic injury in rodents receiving B vitamin supplementation

Lee¹,

Desjardins²,

Sorokin³

et al. 2017

Blood Heart Circ

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Treatment of Ischemic Limbs Based on Local Recruitment of Vascular Endothelial Growth Factor-Producing Inflammatory Cells With Ultrasonic Microbubble Destruction

Abstract: Ultrasonic destruction of microbubbles delivered to the ischemic limbs can recruit inflammatory cells producing VEGF, which is followed by neovascularization and functional improvement, and thus has a therapeutic potential.

Cited by 51 publications

References 27 publications

Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF ₁₆₅ Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle

Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF ₁₆₅ Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle

Association of monoctye expression of Toll-like receptor 4 and its related cytokines with coronary luminal stenosis

Impaired recovery of hind limb muscle perfusion following ischemic injury in rodents receiving B vitamin supplementation

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Treatment of Ischemic Limbs Based on Local Recruitment of Vascular Endothelial Growth Factor-Producing Inflammatory Cells With Ultrasonic Microbubble Destruction

Abstract: Ultrasonic destruction of microbubbles delivered to the ischemic limbs can recruit inflammatory cells producing VEGF, which is followed by neovascularization and functional improvement, and thus has a therapeutic potential.

Cited by 51 publications

References 27 publications

Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF 165 Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle

Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF 165 Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle

Association of monoctye expression of Toll-like receptor 4 and its related cytokines with coronary luminal stenosis

Impaired recovery of hind limb muscle perfusion following ischemic injury in rodents receiving B vitamin supplementation

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Product

Resources

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Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF ₁₆₅ Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle

Therapeutic Arteriogenesis by Ultrasound-Mediated VEGF ₁₆₅ Plasmid Gene Delivery to Chronically Ischemic Skeletal Muscle