Type-2 Diabetic Leprdb/db Mice Show a Defective Microvascular Phenotype under basal conditions and an Impaired Response to Angiogenesis Gene Therapy in the setting of Limb Ischemia
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Diabetes mellitus is associated with macro- and micro-angiopathy, leading to increased risk of peripheral ischemia. In the present study, we have characterized the microvascular phenotype at the level of limb muscles and the spontaneous angiogenesis response to surgically-induced unilateral limb ischemia in a murine model of type-2 diabetes, the obese C57BL/KsOlaHsd-Lepr(db/db) mice (Lepr(db/db)), and in non-diabetic heterozygous Lepr(db/+). Wild type C57BL mice (WT) were used as controls. The basal microvascular phenotype was determined in mice aged 3 or 5 months, while the response to limb ischemia was studied only in 5-month old mice. Moreover, in 5-month old ischemic Lepr(db/db) and Lepr(db/+), we have tested the therapeutic potential of local angiogenesis gene therapy with human tissue kallikrein (hTK) or constitutively-activated Akt kinase (Myr-Akt). We found that in the muscles of 3- or 5-month old Lepr(db/db), apoptosis of endothelial cells was enhanced and the densities of capillary and arteriole were reduced. Arterioles of Lepr(db/db) showed hypertrophic remodelling and, occasionally, lumen occlusion. Following ischemia, Lepr(db/db) showed a defective reparative angiogenesis in ischemic muscle, delayed blood flow recovery, and worsened clinical outcome as compared with controls. Five-month old Lepr(db/+) displayed an increase in endothelial cell apoptosis under basal conditions, while capillary and arteriole densities were normal. Lepr(db/+) mounted a proper reparative angiogenesis response to limb ischemia and regained blood flow to the ischemic limb, regularly. Local gene therapy with hTK or Myr-Akt induced angiogenesis in ischemic muscles of Lepr(db/+) and Lepr(db/db). However, in the Lepr(db/db) neither gene therapy approach improved the blood flow recovery and the clinical outcome from ischemia. In contrast, either hTK or Myr-Akt gene transfer improved the post-ischemic recovery of Lepr(db/+). Type-2 diabetes has a negative impact on the basal microvascular phenotype and severely impairs post-ischemic recovery of limb muscles. Gene therapy-induced stimulation of neovascularization might not suffice as a sole therapeutic strategy to combat type-2 diabetes-related vascular complications. In type-2 diabetic patients, therapeutic angiogenesis may need to be further optimized before being recommended for clinical applications.Keywords:
Basal (medicine)
Limb ischemia
Therapeutic angiogenesis
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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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Angiogenesis is described as a sprouting and growth process of new blood vessels from pre-existing vasculature. The relationship between angiogenesis and coronary artery disease (CAD) is double-sided. On one hand, angiogenesis within plaques is responsible for facilitating the growth and vulnerability of plaques by causing intraplaque hemorrhage and inflammatory cell influx, and overabundance of erythrocytes and inflammatory cells within a plaque probably causes plaque rupture, further leading to acute coronary syndrome. Therefore, inhibiting intraplaque angiogenesis has been considered as a potential therapeutic target for CAD. On the other hand, aiming at improving reperfusion to the ischemic myocardium in patients with CAD, angiogenesis promoting has been utilized as a therapeutic approach to expand myocardial microvascular network. Current strategies include direct administration of angiogenic growth factors (protein therapy), promoting angiogenic genes expression in vivo (gene therapy), and delivering stem cells (cell therapy) or exosomes (cell free therapy). This article will start by clarifying the basic concept of angiogenesis, interpret the mechanism of excessive intraplaque angiogenesis in atherosclerosis, and discuss its role in the growth and vulnerability of plaques. Then we will focus on the four distinct strategies of therapeutic angiogenesis. Despite promising animal studies and smallscale clinical trials of therapeutic angiogenesis in patients with ischemic heart disease, investigations have far not shown definite evidence of clinical efficacy. Hence, while acknowledging future work that remains to be done to validate the clinical results, we reviewed the critical challenges in this arena and highlighted the exciting progress that has occurred recently.
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Angiogenesis is the process of new blood vessel formation, and has potential clinical use in the management of ischemic heart disease. A considerable amount of ongoing research has recently focused on the process of angiogenesis, including the identification of various factors that can inhibit or stimulate this process. The picture that is emerging suggests that a complex set of interactions involving various cells and cellular products is the key to angiogenesis. In particular, endothelial cells and growth factors, such as vascular endothelial growth factor and fibroblast growth factor, appear to play integral roles in angiogenesis. Various preclinical studies involving animal models of ischemia explored the potential use of angiogenesis in ischemic disease. Based on encouraging results, a number of clinical trials involving angiogenesis have been initiated to determine whether the process of angiogenesis also offers therapeutic benefit in humans.
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Peripheral artery diseases remain a serious public health problem. Although there are many traditional methods for their treatment using conservative therapeutic techniques and surgery, gene therapy is an alternative and potentially more effective treatment option especially for "no-option" patients. This review treats the results of many years of research and application of gene therapy as an example of treatment of patients with critical limb ischemia. Data on successful and unsuccessful attempts to use this technology for treating this disease are presented. Trends in changing the paradigm of approaches to therapeutic angiogenesis are noted: from viral vectors to non-viral vectors, from gene transfer to the whole organism to targeted transfer to cells and tissues, from single-gene use to combination of genes; from DNA therapy to RNA therapy, from in vivo therapy to ex vivo therapy.
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Angiogenesis is the process through which new blood vessels are formed, while therapeutic angiogenesis aims to promote and control the angiogenic response. Ischemia results from the lack of blood flow with oxygen and nutrients. Therapeutic angiogenesis is crucial in preserving brain tissue and bodily functions after ischemic stroke. Various approaches have been proposed to promote angiogenesis in ischemic diseases. Traditional protein/gene and subsequent stem/progenitor cell approaches have not shown consistent efficacy for ischemic diseases in clinical trials. Exosomes are microparticles secreted from cells and conduct cell-cell communication including stem cell or cancer cell induced pro-angiogenesis. Utilization of exogenous exosomes for the treatment of ischemic diseases is an emerging approach which may prevent certain disadvantages such as easy degradation and tumor formation happened in other strategies. This review highlights recent reports on the use of exosomes as a therapeutic agent to promote angiogenesis in ischemic stroke.
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