Effectiveness of Mesenchymal Stem Cell-Sheets to Random Pattern Flap in an Experimental Animal Model
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Ischemia of the myocardium and lower limbs is a common consequence of arterial disease and a major source of morbidity and mortality in modernized countries. Inducing neovascularization for the treatment of ischemia is an appealing therapeutic strategy for patients for whom traditional treatment modalities cannot be performed or are ineffective. In the past, the stimulation of blood vessel growth was pursued using direct delivery of growth factors, angiogenic gene therapy, or cellular therapy. Although therapeutic angiogenesis holds great promise for treating patients with ischemia, current methods have not found success in clinical trials. Fibroblast growth factor-2 (FGF-2) was one of the first growth factors to be tested for use in therapeutic angiogenesis. Here, we present a method for improving the biological activity of FGF-2 by codelivering the growth factor with a liposomally embedded coreceptor, syndecan-4. This technique was shown to increase FGF-2 cellular signaling, uptake, and nuclear localization in comparison with FGF-2 alone. Delivery of syndecan-4 proteoliposomes also increased endothelial proliferation, migration, and angiogenic tube formation in response to FGF-2. Using an animal model of limb ischemia, syndecan-4 proteoliposomes markedly improved the neovascularization following femoral artery ligation and recovery of perfusion of the ischemic limb. Taken together, these results support liposomal delivery of syndecan-4 as an effective means to improving the potential of using growth factors to achieve therapeutic neovascularization of ischemic tissue.
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Deficient angiogenesis after ischemia may contribute to worse outcome of peripheral arterial disease in patients with diabetes mellitus. Based on our previous work where we demonstrated that Secretoneurin (SN) is up-regulated under hypoxic conditions and enhances angiogenesis, we analyzed the therapeutic potential of SN gene therapy using a model of severe hind limb ischemia in streptozotocin-induced diabetic mice (STZ-DM). After induction of hind limb ischemia, blood flow was assessed by means of laser Doppler perfusion imaging (LDPI) and increased blood perfusion in the SN-treated animal group was observed. These results were complemented by the clinical observation of reduced necrosis and by an increased number of capillaries and arterioles in the SN-treated animal group. In vitro, we found that SN is capable of promoting proliferation and chemotaxis and reduces apoptosis in HUVECs cultured under hyperglycemic conditions. Additionally, SN activated ERK, eNOS and especially AKT as well as EGF-receptor in hyperglycemic HUVECs. In conclusion, we show that SN gene therapy improves post-ischemic neovascularization in diabetic mice through stimulation of angiogenesis and arteriogenesis indicating a possible therapeutic role of this factor in ischemia-related diseases in diabetic patients.
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The development of blood vessels may be considered in several contexts. Vasculogenesis and angiogenesis are the processes responsible for the development of the circulatory system, the first functional unit in the developing embryo (1). Pathologic angiogenesis includes the role of post-natal neovascularization in the pathogenesis of arthritis, diabetic retinopathy, and, most notably, tumor growth and metastasis (2). Therapeutic angiogenesis involves the development of collateral blood vessels supplying ischemic tissues, either endogenously or in response to administered growth factors. The purpose of this review is to consider the mechanisms responsible for therapeutic angiogenesis, which develops endogenously, as well as novel strategies, which have been devised to augment this response. Because recapitulation of the embryonic paradigm forms the conceptual basis for therapeutic, as well as pathologic angiogenesis, selected aspects of embryonic blood-vessel development are included. While pathologic angiogenesis is beyond the scope of the current paper, certain principles which have emerged from studies of pathologic neovascularization are considered for the implications they may have for cardiovascular disease.
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AimsUnsatisfactory effects of therapeutic angiogenesis in critical limb ischaemia may be ascribed to use of circulating angiogenic cells (CACs) derived from atherosclerotic patients with impaired neovascularization-related capacities. We tested whether ultrasound cell stimulation can restore the impaired capacities.
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Therapeutic angiogenesis constitutes a fundamental survival mechanism that acts to preserve the integrity of tissues subjected to ischemia. Supplemental administration of angiogenic cytokines - as recombinant protein or plasmid DNA - have been shown to augment collateral development when endogenous angiogenesis is suboptimal for organ function, and thus constitute a novel therapeutic option for the treatment of cardiovascular disease. These angiogenic cytokines, all of which share in common the ability to act as mitogens for endothelial cells, do not promote angiogenesis in an indiscriminate fashion; thus angiogenic cytokines selectively produce neovascularization in the ischemic tissues. The purpose of this review is to consider the mechanisms responsible for therapeutic angiogenesis which develops endogenously as well as strategies which have been devised to augment this response. The development of blood vessels is considered from the context of the embryonic paradigm; certain principles which have emerged from studies of pathologic neovascularization; and, principally, the development of collateral blood vessels supplying ischemic tissues, either endogenously or in response to administered growth factors.
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Therapeutic angiogenesis is an effective means for tissue salvage in patients with critical limb ischemia. Angiogenesis is defined as a formation of new blood vessels by sprouting of preexisting mature endothelial cells(ECs). In contrast, vasculogenesis is referred to as the creation of primordial blood vessels from endothelial progenitor cells (EPCs) or angioblasts. Neovascular formation in adults has been considered to result exclusively from the former process(i.e., angiogenesis). However, we and other researchers recently identified EPCs in human peripheral blood(PB), and circulating EPCs have been shown to accumulate at active angiogenic sites and to participate in neovascularization, a notion consistent with 'postnatal vasculogenesis'. EPCs in adults originate from bone marrow(BM), and we recently have demonstrated that in vivo implantation of autologous BM-MNCs effectively augmented ischemia--induced neovascularization in animal studies as well as human trial(TACT Trial). Here we summarize recent advances in cell transplantation-mediated therapeutic angiogenesis.
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Objective— Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization. Methods and Results— In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice. Conclusions— NP-m...
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Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization.In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice.NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.
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Corneal Neovascularization
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The basis for native as well as therapeutic neovascularization is not restricted to angiogenesis but includes postnatal vasculogenesis. Our laboratory and others’ have established that bone marrow‐ derived endothelial progenitor cells (EPCs) are present in the systemic circulation, are augmented in response to certain cytokines and/or tissue ischemia, and home to as well as incorporate into sites of neovascularization. Given the background, EPCs have been investigated as therapeutic agents in these studies of supply-side angiogenesis under pathological as well as physiological conditions. This review discusses the therapeutic potential of EPCs for cardiovascular ischemic diseases.
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