Current Vascular Pharmacology - Volume 8, Issue 2, 2010

Platelets are key mediators of thrombosis. Drugs that interfere with platelet activation substantially improve survival in arterial thrombotic disease. One attractive family of drug targets which has already been exploited in the development of antiplatelet agents are G-protein coupled receptors (GPCRs). Yet limitations of present antiplatelet agents, including incomplete efficacy, bleeding and drug resistance, have spurred the development of new drugs directed at alternative platelet GPCRs. Compounds that target platelet receptors including P2Y12, protease-activated receptor-1 (PAR1), the thromboxane A2 receptor (TP receptor), the prostaglandin receptor (EP3 receptor), and the serotonin receptor (5-HT2A receptor) have been identified and are in various phases of clinical development and use. Yet, improving the clinical profile of reagents targeting platelet GPCRs may not be only a matter of blocking alternative GPCRs. A more detailed understanding of GPCR function is leading to the development of pharmacophores with novel mechanisms of drug action. Identifying compounds that work by alternative mechanisms may be equally or more valuable than developing reagents targeting different GPCRs. Pharmacological concepts such as GPCR oligomerization, allosterism, and targeting GPCR-G protein interactions may ultimately provide opportunities to more effectively control platelet activation in the clinical setting. In this review, we will discuss the utility and limitations of GPCR-targeted antiplatelet therapies in clinical use and development. We will also consider emerging concepts in GPCR pharmacology that have the potential to foster the development of GPCR-targeted reagents with novel mechanisms of action and improved clinical profiles.

Obesity is associated with increased cardiovascular disease (CVD) risk, especially when excess body fat is distributed preferentially within the abdominal region. Obese subjects usually have increased arterial stiffness compared with non-obese subjects of similar age. The factors associated with increased arterial stiffness in obesity include endothelial dysfunction (decreased nitric oxide bioavailability), impaired smooth muscle cell function, insulin resistance, as well as elevated cholesterol and C-peptide levels. Furthermore, visceral fat, the adipose tissue-related renin-angiotensinaldosterone system and hyperleptinaemia contribute to the obesity-associated impaired arterial compliance. Weight loss improves CVD risk factors and arterial compliance. Because increased arterial stiffness is a marker of CVD risk these findings support the concept that the presence of obesity has vascular implications.

Nowadays long-term outcome of heart transplantation is limited by a peculiar type of coronary atherosclerosis, known as cardiac allograft vasculopathy (CAV). Although the exact pathogenesis of CAV remains unclear, emerging evidence indicates that the endothelium plays a significant role in the onset and progression of this disease. Nitric oxide (NO) is the principal mediator of all endothelial protective effects, due to its antinflammatory, antiproliferative, immunomodulatory and vasorelaxant properties. CAV involves immunologic mechanisms operating in the context of common cardiovascular risk factors which lead to impaired endothelial function, mainly as a consequence of decreased NO bioavailability and excessive oxidative stress. Once dysfunctional, the endothelium promotes CAV lesion progression towards the diffuse narrowing of the coronary vasculature which characterizes advanced allograft vasculopathy. Recently, many studies showed the possibility to restore endothelial dysfunction with an associated potential improvement in clinical cardiovascular outcome. Therefore, growing interest deserves the possibility to exert an endothelial protective role shown by some currently used cardiovascular and immunosuppressive drugs, as well as the future development of new pharmacological compounds with selective endothelial protective properties as a target for successful prevention and therapy of CAV.

Diabetes mellitus is a leading cause of morbidity and mortality because of its cardiovascular complications. It has been suggested that hyperglycemia, hyperinsulinemia and insulin resistance, glycation of proteins, oxidative stress, inflammation, and many other factors may be related to atherogenesis in diabetes. The metabolic abnormalities associated with diabetes lead to activation of the renin-angiotensin-aldosterone-system (RAAS), with a subsequent increase of angiotensin II and aldosterone levels, which might alter the insulin signaling pathway and promote the formation of reactive oxygen species that induce endothelial dysfunction as well as cardiovascular disease and renal disease. Synthesis of angiotensin II is not only catalyzed by angiotensin-converting enzyme, but also by chymase. Recently, angiotensin II produced by chymase was reported to be involved in vascular proliferation and atherosclerosis. Chymase also activates matrix metalloproteinase- 9, leading to extracellular matrix degradation, and promotes cardiovascular remodeling. Many studies have shown that angiotensin-II blockade significantly reduces the levels of proinflammatory mediators and suppresses oxidative stress. In clinical trials, RAAS blockade has been found to delay or prevent the onset of type 2 diabetes, and it also prevents cardiovascular and renal events in diabetic patients. Thus, RAAS inhibition represents first-line treatment for hypertensive and diabetic target organ damage, as well as preventing the progression of cardiovascular disease and kidney disease. This review presents the available information about the role of the RAAS in the cardiovascular and renal complications of diabetes.

Neointima (NI) formation following arterial bypass graft surgery or balloon angioplasty is considered central to subsequent failure after these procedures. The NI promotes accelerated atherogenesis, re-occlusion and thrombosis resulting in a failure rate as high as 50% within 1-10 years. Furthermore, despite the relative success of statins and drug eluting stents, drugs that reduce the failure rate have as yet not been implemented. In turn, animal models are a crucial means of testing potential interventions, in particular, drugs. The objective of this review therefore is to provide a survey of all the possible models that can be used to explore the effects of drugs on NI formation. The review will focus on the most commonly used of species, namely the rat, rabbit, mouse, pig and dog.

The neo-angiogenesis process is crucial for solid tumor growth and invasion, as the vasculature provides metabolic support and access to the circulation. Tumor blood vessels differ from normal vessels by altered morphology, blood flow and permeability, and the “switch” of endothelial cells to an angiogenic phenotype is considered a hallmark of the malignant process. Recent evidence indicates that tumor-derived endothelial cells (TEC) possess a distinct and unique phenotype differing from normal endothelial cells at the molecular and functional levels. The anti-angiogenic therapies developed to date are based on tumor endothelial cells being genetically normal. However, it has recently been shown that TEC derived from different tumors are genetically unstable and may acquire resistance to drugs. It has been suggested that TEC may acquire cytogenetic abnormalities within the tumor microenvironment. We found that TEC from different tumors share characteristics in terms of pro-angiogenic properties, survival and resistance to chemotherapy in respect to non-tumor endothelial cells and maintain in vitro an immature pro-angiogenic phenotype in the absence of tumor cells. This was associated with an up-regulation of the AKT/PI3K pathway, involved in the repression of the anti-angiogenic factors thrombospondin-1 and PTEN, and the presence in TEC of the embryonic transcription factor PAX2, responsible for the expression of immature endothelial markers such as NCAM. The in vivo inhibitions of these pathways were shown to display an anti-angiogenic effect on TEC. This review considers the current studies on TEC abnormalities and discusses the hypothesis that at least part of tumor vessels may derive from an intra tumor ongoing embryonic-like vasculogenesis or from tissue endothelial cells switched to angiogenesis from genetic information transmitted from the tumor.

Atherosclerosis is a chronic inflammatory disease involving many cell types with a well-accepted key role for macrophages. A wide array of different properties and functional characteristics are attributed to macrophages present in the atherosclerotic plaque. As an increasing body of evidence strengthens the consensus that macrophages comprise a heterogeneous population, several co-existing subtypes with diverse, even opposing specialties have already been described in fields like parasitology, tumour biology and metabolic disorders. However, macrophage heterogeneity within atherosclerotic lesions has not been studied in detail yet. In this review we will introduce the characteristics of macrophage subsets in other pathologies and address the presence and possible roles of distinct macrophage subtypes in the rapidly evolving field of atherosclerosis. Finally, we make an effort to relate these subtypes to disease progression and explore a number of opportunities for novel diagnostic and therapeutic approaches.

The incidence of cardiovascular disease is low in healthy premenopausal women and increases with age especially after the menopause; this difference has been attributed to the loss of endogenous estrogen. Atherosclerosis is a chronic inflammatory condition of the vascular wall that may result in an acute clinical event by inducing plaque rupture/ erosion leading to thrombosis. A growing body of evidence suggests that the spectrum of the effects of estrogen on vascular pathophysiology is complex and may depend largely on the state of vascular pathology. In relatively healthy vessels, estrogen prevents the development and progression of atherosclerotic lesions, while in the presence of established atherosclerotic plaques, estrogen fails to inhibit the progression of atherosclerosis or may even trigger cardiovascular events. The mechanisms responsible for this are not yet fully elucidated. It is possible that postmenopausal estrogen/ progestogen therapy may be beneficial in perimenopausal and early menopausal women prior to atherosclerotic plaque formation, but it may not prevent progression of atherosclerotic plaques and acute cardiovascular events in older women with cardiovascular risk factors or women with established atherosclerosis. Various formulations, doses and routes of hormone therapy administration as well as the genetic background of women should also be taken into account when considering the benefit-to-risk ratio of hormone therapy use.

There is evidence that reactive oxygen species (ROS) are related to the development of cardiovascular disease (CVD). Results from many studies support the hypothesis that ROS released from various sources or dysfunctional mitochondrial respiratory chain play a role in the development of atherosclerosis and its complications. This phenomenon is due to ROS-mediated signalling pathways that are involved in the modulation of several vascular mechanisms. Various animal models have demonstrated that ROS have a causal role in atherothrombosis and other vascular diseases. Oxidative stress is being proposed as the unifying mechanism for many CVD risk factors. In particular, ROS may be responsible for plaque rupture and subsequent thrombosis which lead to myocardial infarction and stroke. Many drugs or agents have been tested to prevent or block oxidation underlying atherothrombotic processes, often with discordant outcomes. We observed that pre-treatment with some antioxidants, such as pyrrolidine dithiocarbamate (PDTC) or N-acetylcysteine, as well as some vitamins with recognized antioxidant properties, namely ascorbic acid (vitamin C), all-trans Retinoic Acid (atRA) and α-tocopherol (vitamin E) can suppress oxidative stress (OS)-induced Tissue Factor (TF) expression in human coronary artery endothelial cells. The present review, starting from our experimental observations, focuses on the influence of redox balance on atherothrombotic processes and on the effects of antioxidant treatment. A better understanding of the complex regulation of cellular redox balance could facilitate the development of newer antioxidants aimed at specific cellular targets. Research could also help assess the role of combination pharmacological intervention for the treatment and prevention of vascular disease.

The major aim of this review was to ascertain whether effective evidence-based treatments for acute coronary syndromes (ACS) are underutilized in women in various geographic areas compared with men. The focus of our review was the relative use of effective treatments in patients with coronary angiographic evidence of obstructive coronary disease, defined as a lumen stenosis >50% of the adjacent non-diseased arterial diameter. We searched MEDLINE, and the Cochrane Database between January 1998 and May 2008. Only a few of the published clinical registries on ACS provide data on treatments dichotomized by confirmed coronary angiographic disease. Consequently, we also accessed individual patient-level data from 3 established ACS registries: the Finnish TACOS (Tampere Acute COronary Syndrome), the British EMMACE 2 (Evaluation of Methods and Management of Acute Coronary Events) and the Argentine PACS-ITALSIA (Prognosis in Acute Coronary Syndromes and the ITALian hospital Sindrome Isquemico Agudo). Despite presenting with higher risk characteristics and having higher in-hospital and 6 months risk of death, women with ACS and obstructive coronary artery disease were apparently treated less aggressively with secondary preventive drugs than were men, being less likely to receive aspirin, beta-blockers and statins at discharge. Overall, coronary revascularization appears to be performed in a similar proportion of women and men - once angiography has been performed and the coronary anatomy is known. However, substantial geographic variation exists in the relative rate of coronary angiography in men and women. In United Kingdom coronary revascularization tends to be done less frequently in women. Our study, therefore, demonstrates a gender bias in the delivery of secondary drug treatments for ACS, even for patients with documented significant coronary disease.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects about 1% of the adult population. RA sufferers not only have a high chronic disease burden, but may also experience increased cardiovascular disease (CVD) and mortality as the prevalence of myocardial infarction (MI) is 4 times higher in RA patients than in general population, and there is ample evidence showing that coagulation processes are active in RA. Fibrin accumulation in the synovium is one of the most striking pathological features of rheumatoid synovitis and characteristic RA antibodies such as anti-citrullinated protein antibodies (ACPA) can cross-react with epitopes exposed on fibrin and fibrinogen molecules, and thus impair fibrinolysis. The inflammation, coagulation and fibrinolytic systems are modulated by a common mechanism that includes the involvement of proinflammatory cytokines, such as tumour necrosis factor-α (TNF-α) and interleukin 6 (IL-6). It has long been recognised that extensive cross-talk takes place between the coagulation pathway and the inflammatory process at various levels, and there is growing evidence that this interaction may be relevant to arthritis. Large-scale, long-term studies have shown that anti-TNF-α treatment improves the clinical and laboratory measures of disease activity, and reduces local and systemic inflammation. TNF-α blockade may therefore also reduce the impaired coagulation and cardiovascular risk associated with RA. This review provides an overview of the pathophysiological role of TNF-α in thrombotic mechanisms and the evidence so far available indicating that anti-TNF-α treatment can modify cardiovascular risk in RA.