Current Pharmaceutical Design - Volume 14, Issue 4, 2008

Vascular disease is a major cause of morbidity and mortality worldwide. Reducing the incidence of deaths due to vascular causes holds implications for national economies worldwide [1]. On this basis, several animal models have been developed to replicate human vascular diseases in order to study their pathophysiology. This issue of the Current Pharmaceutical Design discusses some of these models. In this Editorial we will briefly review each article in this Special Issue and we will also briefly consider a few additional models. Thompson describes various animal models of diabetes and also highlights those most commonly used to evaluate diabetic micro- and macrovascular complications [2]. Paraskevas et al. describe the animal models developed for the study of abdominal aortic aneurysms (AAAs) [3]. This review focuses on the pathomechanisms involved in the development of AAAs and the different treatment modalities for their management. Kolovou et al. describe apolipoprotein E (Apo E) knock out mouse models, which were developed to study atherosclerosis and cardiovascular diseases [4]. The applications of these models in the study of lipoprotein metabolism, arterial wall stiffness and the effect of various diets/ drugs are also discussed. Tatlisumak et al. describe the various animal models for the study of the pathophysiology and management of stroke. In one review, they discuss rodent models of hemorrhagic stroke [5]. In the second review, they discuss models of ischemic stroke [6]. They provide a detailed analysis of why these animal models are important for our understanding of the pathophysiology of stroke and brain ischemia and how they can be used to discover (and test) novel treatment strategies. The advantages and disadvantages of each reported model are also outlined. Shiba et al. describe models of angiogenesis [7]. They discuss the mechanism of neovascularization and the applications of therapeutic angiogenesis in humans based on animal models. Xirouchakis et al. describe experimental models of non-alcoholic fatty liver [8]. This condition is associated with both metabolic syndrome and diabetes. Inevitably therefore, there is a link between fatty liver and an increased risk of vascular disease. In addition, several other models have been developed for the study of vascular disease. This Editorial briefly addresses some of them. Peripheral Arterial Disease (PAD) Several animal models for the study of PAD have been described. Lower limb ischemia affects a large percentage of the population. One of the most rapidly growing treatment modalities for the management of PAD is therapeutic angiogenesis [9]. Animal models of hindlimb ischemia were developed to evaluate the beneficial effects of autologous bone marrow cell infusion [10,11], vascular endothelial growth factor (VEGF) [12] and platelet-derived endothelial cell growth factor (PD-ECGF) [13] for the induction of angiogenesis. Other models were developed for the establishment of diagnostic tests for the evaluation and quantification of angiogenesis [14-17]. These models provide insight in the pathophysiology and management of PAD. Application of these preliminary results in humans holds implications for a different therapeutic approach. Hyperhomocysteinemia Hyperhomocysteinemia has been proposed as an independent risk factor for atherothrombotic disease [18-20]. Supplementation with methionine, homocysteine and/or depletion of folic acid and B vitamins can induce mild to severe hyperhomocysteinemia [21,22]. Mice with a heterozygous cystathione β-synthase-deficiency (enzymes responsible for homocysteine metabolism) develop endothelial dysfunction by decreasing vascular nitric oxide bioavailability, thereby leading to impaired vasorelaxation [23,24]. Animal models of hyperhomocysteinemia have extended many of the proposed mechanisms linking this abnormality with atherogenesis. However, the findings reported in animal models are not necessarily reproduced in human studies [25]. Hypertension Hypertension is an important risk factor for cardiovascular and cerebrovascular disease. Research on pathophysiology and treatment of hypertensive brain damage may benefit from the availability of animal models [26-30]. Spontaneously hypertensive rats represent the most commonly used animal model. In these rats, cerebrovascular changes, brain atrophy, loss of nerve cells in cerebrocortical areas and glial reaction occur. The influence of anti-hypertensive treatment on brain structure and function in animal models of hypertension has also been investigated [26-30]..........

The prevalence of diabetes mellitus is increasing worldwide at an alarming rate due to population growth, obesity, sedentary lifestyle and aging. Consequently, diabetic microvascular complications (retinopathy and nephropathy) and macrovascular complications (coronary heart disease, peripheral arterial disease and cerebrovascular disease) are also rising. Traditional oral hypoglycaemic agents only partially prevent the development of these complications. This suggests that selective treatment options that target specific biological pathways (i.e. metabolic factors, intracellular signaling proteins and growth factors) may be a more effective strategy. Type 1 and Type 2 diabetic animal models have been produced spontaneously by selective inbreeding or by genetic modification, as well as, pharmacological induction. These models have become a safe and reliable option to test the therapeutic potential of novel drugs. They also help to understand the pathophysiology of diabetes mellitus. This review highlights the most commonly used animal models for the treatment of diabetic micro and macrovascular complications.

In the last 50 years, several experimental models of abdominal aortic aneurysms (AAAs) have been described. These models have aided scientists and physicians to understand the pathophysiological mechanisms underlying AAA development and progression. In addition, they have served as means for the development of a number of conservative (such as doxyxycline, marimastat and propranolol) and surgical treatment options for the management of AAAs. In the last few years, experimental models have contributed in the development of novel endovascular techniques for the treatment of AAAs. Animal models of endovascular grafts and percutaneous techniques comprise an essential step for the successful clinical application of these procedures. Additionally, they may comprise part of the training process for vascular surgeons. The different experimental AAA models are briefly presented and their clinical significance is discussed. Experimental models play an essential role in the field of research for the development of more successful therapeutic alternatives for the management of AAAs.

Atherosclerosis is a multifactorial and long-lasting process in humans. Therefore, animal models where more rapid changes occur can be useful for the study of this process. Among such models are the apolipoprotein (apo) E knock out mice. Apo E deficient mice show impaired clearing of plasma lipoproteins and they develop atherosclerosis in a short time. The current review considers lipid metabolism and inflammation as well as nutritional and pharmacological agents affecting atherosclerosis, using the apo E knock out mouse model.

Both intracerebral and subarachnoid hemorrhages are associated with high mortality and most survivors are burdened with severe disability. Currently, there is no approved treatment for intracerebral hemorrhage and surgical evacuation was not proven beneficial. Regarding subarachnoid hemorrhage, existing therapies need substantial improvement. Detailed pathophysiologic mechanisms need to be understood in order to develop novel therapeutic strategies. Hemorrhagic stroke models can help achieve both these goals and answer those questions that cannot be addressed in the clinical setting. There are several animal models of intracerebral and subarachnoid hemorrhage, each mimicking fairly reliably different aspects of the condition studied. The similarities and differences among the existing rodent models, model modifications, and some aspects concerning the choice of relevant model are discussed.

Stroke is the third common cause of death and the most common cause of adult disability. Approximately 80% of all strokes are ischemic (brain infarction). The only approved acute therapy is intravenous thrombolysis with tissue plasminogen activator within 3 h of symptom onset but only a small percentage of all ischemic stroke patients can receive this therapy. Therefore, novel therapeutic approaches directed at the pathophysiological mechanisms involved in ischemic brain injury are urgently needed. To this end several experimental stroke models were developed. These models are indispensable for understanding the pathophysiology of brain ischemia and to develop novel drugs and investigative methodology. This review considers the most commonly used ischemic stroke models (including preconditioning models) in rodents emphasizing their advantages and disadvantages. Since none of the models can perfectly simulate human stroke, researchers must interpret experimental findings carefully.

Cardiovascular disease remains a principal cause of mortality in Western countries. Novel strategies for enhancing angiogenesis (such as gene or cell therapy) provide alternative choices for patients without any current treatment options. This progress has contributed towards understanding the mechanisms underlying vascular formation. The establishment of new experimental models could lead to the development of new treatments. This article overviews the diverse models for the study of angiogenesis.

Non alcoholic fatty liver disease (NAFLD) is often part of the metabolic syndrome which includes central obesity, dyslipidaemia, insulin resistance/type 2 diabetes mellitus and hypertension. In turn, NAFLD may be associated with an increased vascular risk. Several experimental models which express histological steatosis or steatohepatitis with fibrosis have been described. This review identifies those models of NAFLD with features of vascular risk.

HIV cellular entry is a multistep process that requires the interaction of a viral envelope glycoprotein (gp120) and a host receptor (CD4) followed by binding to a co-receptor. The CC-chemokine receptor 5 (CCR5) and CXC-chemokine receptor 4 (CXCR4) have been identified as the major HIV co-receptors and therefore are promising targets for the development of new anti-HIV drugs. CXCR4 is also involved in several diseases such as angiogenesis, metabolic and neurological disorders, rheumatoid arthritis and in different forms of metastatic cancer. Herein, we present a review focusing on small molecule CXCR4 antagonists. These compounds are divided into 11 classes that include cyclic penta- and tetrapeptides, diketopiperazine mimetics, bicyclams, non-bicyclams, tetrahydroquinolines, thiazolylisothiourea derivatives, benzodiazepines, alkyl amine analogs and non-peptides derivatives, dipicolylamine-zinc(II) complexes, ampelopsin and distamycin analogs. The most advanced CXCR4 antagonists documented are bicyclam derivatives, which are specific CXCR4 antagonists and exhibit potency in the nanomolar range. Further development of selective CXCR4 antagonists continues to be crucial for the design of second generation of anti-HIV drugs. We aim to provide a comprehensive summary of diverse structural templates that could be useful for optimization and discovery of novel CXCR4 antagonists.

Due to the fact that the percentage of aged subjects in the populations of industrialized countries is dramatically increasing, the scientific community has been obligated to focus their attention on age related disease states and peculiar consequences of aging such as, frailty. Frailty is defined as a syndrome of decreased reserve and resistance to stressors and is clinically expressed as muscle weakness, poor exercise tolerance, factors related to body composition, sarcopenia, and lower extremity mobility. Some biochemical markers of frailty in older persons, including pro-inflammatory markers, hormones and free radicals have been suggested. However, there is growing evidence that a rise in insulin resistance [IR] occurs as individuals age and IR is not only considered a simple metabolic finding, but has been identified as a major risk factor for many age-related diseases due to altered lipid metabolism, increased inflammatory state, impaired endothelial functioning, pro-thrombotic status and atherosclerosis. Considering that IR is related to many of the clinical features of frailty such as, skeletal muscle weakness, lower extremity mobility disability, cognitive decline and body composition changes, we will analyze the relationships among IR and such individual components while highlighting potential pathophysiologic mechanisms of IR on the activation of the downward spiral of the frailty syndrome in older persons. In particular, we will address the issue that IR may also be considered a pivotal biological component of some clinical aspects of the frailty syndrome in aging individuals.