Current Vascular Pharmacology - Volume 10, Issue 1, 2012

Current Vascular Pharmacology (CVP) has come a long way 10 years after its launching. We obtained listing on MEDLINE several years ago and our impact factor is now 3.184 [Institute of Scientific Information (ISI) website]. This places us on the top 16% of all journals listed on the ISI website. Most medical journals do not even achieve listing on that website. This year, we already have a very interesting choice of articles that cover a wide field of vascular pharmacology. In this issue, the “Hot Topic” is endothelial function. We have other hot topic issues coming during the year as well as general articles. These include, themes like statin-induced myopathy, smoking, diabetes, hypertension, metabolic syndrome and thrombosis. One innovation during 2011 was that we now consider original research papers as well as reviews and editorials. However, these original research papers will be restricted to 20% of the journal content. Thus, CVP remains primarily a review journal. We prefer original research papers to be focused on human studies; however, we can make exceptions. We always try to be as flexible as possible (within reason!). Therefore, we also do not impose strict restrictions with regard to how many words or references are allowed. Another novel feature for CVP was that we publish guidelines (e.g. European Society of Vascular Surgery - carotid disease prevention) and Expert Panel statements (e.g. regarding “small, dense low density lipoproteins” and “post-prandial lipaemia”)….

During the last decade, it has been well documented that the vascular endothelium is not only a monolayer of endothelial cells (ECs) that lines the entire vascular system, but also it contributes actively to vascular homeostasis, inflammatory and immune responses [1]. More specifically, it has been found that endothelial cells exert significant autocrine, paracrine or endocrine actions and affect platelets, smooth muscle cells, as well as leucocytes. Also, it constitutes a crucial border between the circulation and the interstitium/cells, while regulating the vascular tone, inducing the production of several vasoactive substances including nitric oxide (NO), endothelin (ET), angiotensin II and endothelial-derived hyperpolarizing factor (EDHF) [2, 3]. Therefore, it is obvious that endothelial dysfunction plays a key role in the progress of atherosclerosis. Studies have reported that a several factors-conditions including hyperlipidemia, hypertension, hyperhomocysteinemia, smoking, diabetes mellitus, and genetic factors predispose to endothelial dysfunction (ED) [4-6]. Additionally, novel risk factors have been determined the last years that are closely related to the incidence and prevalence of cardiovascular disease. Among others, C-reactive protein, homocysteine, and myeloperoxidase, have gained wide interest [7-9]. Whilst these biomarkers derive from very different pathways, they all affect the normal endothelial function. Beyond that, asymmetrical dimethylarginine (ADMA) has evolved as an important regulator of NO synthesis and is the first cardiovascular biomarker that acts primarily by impairing NO-mediated endothelial function [8]. Asymmetrical dimethylarginine thus is a marker that may be useful during the early stages of atherosclerosis. Moreover, considering the fact that endothelial dysfunction is a major mechanism participating in all the stages of atherosclerosis requires an in depth, evaluation of endothelial function as it appears to have a predictive role in humans [2], and therapeutic interventions improving nitric oxide bioavailability in the vasculature, may improve the long-term outcomes in healthy individuals, high-risk subjects or patients with advanced atherosclerosis. Therefore, several therapeutic strategies have been investigated and proposed to targeting both the synthesis and production of NO in human vasculature. The first paper by Tousoulis et al. [10] is an introductory one, discussing thoroughly the role of nitric oxide in ED, highlighting associated pathways and mentioning the need for therapeutic approaches improving vascular function….

The vascular endothelium is a monolayer of cells between the vessel lumen and the vascular smooth muscle cells. Nitric oxide (NO) is a soluble gas continuously synthesized from the amino acid L-arginine in endothelial cells by the constitutive calcium-calmodulin-dependent enzyme nitric oxide synthase (NOS). This substance has a wide range of biological properties that maintain vascular homeostasis, including modulation of vascular dilator tone, regulation of local cell growth, and protection of the vessel from injurious consequences of platelets and cells circulating in blood, playing in this way a crucial role in the normal endothelial function. A growing list of conditions, including those commonly associated as risk factors for atherosclerosis such as hypertension, hypercholesterolemia, smoking, diabetes mellitus and heart failure are associated with diminished release of nitric oxide into the arterial wall either because of impaired synthesis or excessive oxidative degradation. The decreased production of NO in these pathological states causes serious problems in endothelial equilibrium and that is the reason why numerous therapies have been investigated to assess the possibility of reversing endothelial dysfunction by enhancing the release of nitric oxide from the endothelium. In the present review we will discuss the important role of nitric oxide in physiological endothelium and we will pinpoint the significance of this molecule in pathological states altering the endothelial function.

Patients with diabetes mellitus (DM) have a high prevalence of coronary artery disease (CAD), as diabetes is implicated in the formation of atherosclerotic plaque. Endothelial dysfunction is one of the precursor key steps in the development of atherosclerosis in diabetic subjects. Decreased nitric oxide (NO) production, increased oxidative stress and impaired function of endothelial progenitor cells are the main mechanisms involved in the accelerated atherosclerotic process observed in type 2 DM patients. Therapeutic approaches including classic agents such as statins, angiotensinconverting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), antioxidants and novel agents such as tetrahydrobiopterin (BH4), asymmetric dimethylarginine (ADMA) and homocysteine (tHcy), have been implicated in order to ameliorate endothelial function of diabetic patients.

Endothelial dysfunction represents an important step in the pathogenesis of atherosclerosis. All vascular risk factors can induce endothelial dysfunction, which in turn results in the loss of the protective effects of the endothelium culminating in the development of atherosclerosis. Dyslipidemia is a major vascular risk factor and is associated with endothelial dysfunction. Several studies showed that lipid-lowering agents exert beneficial effects on endothelial function in different populations at increased vascular risk, including patients without dyslipidemia. Therefore, other actions besides lipid-profile modification appear to be implicated in this benefit. However, it is unclear whether the improvement in endothelial function independently contributes to the vascular risk reduction during lipid-lowering treatment (e.g. with statins). It is also unclear whether the assessment of endothelial function would help identify patients who require more aggressive lipid-lowering treatment.

A large body of evidence indicates that patients with essential hypertension are characterized by endothelial dysfunction mediated by an impaired NO availability secondary to oxidative stress production. A dysfunctioning endothelium is an early marker of the development of atherosclerotic changes and can also contribute to cardiovascular events. Vascular reactivity tests represent the most widely used methods in the clinical assessment of endothelial function. In the last two decades, many studies have evaluated the endothelium in hypertensive patients, using different techniques. Several methodologies were developed to study microcirculation (resistance arteries and arterioles) and macrocirculation (conduit arteries), both in coronary and peripheral vascular districts. This review will describe the most relevant available techniques in the research on endothelial dysfunction in essential hypertension, their advantages and limitations, focusing on available data on endothelial dysfunction and on the effect of treatment. Endothelial dysfunction in the coronary and peripheral circulation of hypertensive patients are associated with hypertensive target organ damage and it is predictive of cardiovascular events. Several non-pharmacological approaches, including physical exercise and dietary interventions, can ameliorate endothelial function in hypertensive patients. Despite blood pressure reduction per se is not effective, some antihypertensive drugs can improve endothelial dysfunction, particularly calcium channel antagonist in the microcirculation, ACE-inhibitors and AT1-receptor antagonists mostly in conduit arteries. Some beneficial effects were also exerted by nebivolol and statins. Future studies are needed to confirm whether the improvement in endothelial dysfunction is associated to better cardiovascular prognosis in hypertension.

Nitric oxide (NO) is a soluble gas continuously synthesized from the amino acid L-arginine in endothelial cells by the constitutive calcium-calmodulin-dependent enzyme nitric oxide synthase (NOS). Endothelial dysfunction has been identified as a major mechanism involved in all the stages of atherogenesis. Evaluation of endothelial function seems to have a predictive role in humans, and therapeutic interventions improving nitric oxide bioavailability in the vasculature, may improve the long-term outcome in healthy individuals, high-risk subjects or patients with advanced atherosclerosis. Several therapeutic strategies (including statins, angiotensin converting enzyme inhibitors/angiotensin receptors blockers, insulin sensitizers, antioxidant compounds) are now available, targeting both the synthesis and oxidative inactivation of NO in human vasculature, reversing in that way endothelial dysfunction which is enhanced by the release of nitric oxide from the endothelium.

Persistent oxidative stress in the vascular wall may lead to endothelial dysfunction, a pathological process widely implicated in the morbidities observed in a spectrum of cardiovascular disease. The production of reactive oxygen species (ROS) is regulated by various oxidase enzymes and mitochondrial electron transport mechanisms. Nitric oxide (NO) is a key mediator of endothelial function via its effect on endothelium dependent vascular relaxation. Therapeutic interventions aimed to increase NO bioavailability in the vasculature may improve the long term cardiovascular outcome for healthy individuals, high-risk subjects, and patients with advanced atherosclerosis. Current therapeutic strategies focus on enhancing synthesis or lowering oxidative inactivation of NO in human vasculature. Of the available therapeutic agents, angiotensin converting enzyme inhibitors and statins have shown most promise at improving endothelial function and cardiovascular outcome after long term administration. Other therapeutic approaches may also be useful towards improving endothelial dysfunction. These strategies include targeting NO synthesis by modulation of endothelial nitric oxide synthase (eNOS) coupling, such as folates and tetrahydrobiopterin. Evidence for the benefits of gene therapy to improve endothelial function is also emerging. However, the long term direct clinical benefit of these strategies aimed to improve endothelial function still remains unclear.

Atherosclerotic disease remains a major health problem around the world. The central role of endothelium and inflammation in all stages of the atherosclerotic process is advocated by significant data. Moreover, clinical evidence supports the prognostic potential of endothelial dysfunction for the development of ischemic events and for adverse outcome after acute coronary syndromes. Interestingly, suboptimal lifestyle choices are implicated in the development and deterioration of this endothelial dysfunction, a fact with significant impact, considering the contribution of endothelial dysfunction in atherosclerosis and its complications. Many epidemiological research studies, using a variety of strategies, provide encouraging evidence suggesting that lifestyle modifications may have significant impact regarding the improvement of endothelial function. However, little is known about how individual's genetic background interacts with environmental influences on vascular health, thereby making the interpretation of the relative importance of lifestyle interventions more complicated.

Cardiovascular atherosclerotic and ischemic diseases constitute the leading cause of morbidity and mortality throughout middle- and high-income countries. More efficient preventive and regenerative therapeutic strategies are therefore urgently needed. The repeated finding that putative “endothelial progenitor cells” (EPCs) can efficiently promote angiogenesis and restore perfusion of ischemic tissues has provoked a wealth of studies evaluating and developing their therapeutic potential. In the present review, we discuss the growing knowledge about various distinct cell populations which have been collectively termed “EPCs”, including myeloid cells and progenitor cells of different origin. We also present clinical studies aiming to examine their therapeutic potential for cardiovascular disease. In addition, we will discuss recent insights into mechanisms leading to dysfunction of “EPCs” in cardiovascular disease. Those findings may help to optimize autologous cell-based treatment approaches, as well as to establish cellular dysfunction itself as an interesting novel therapeutic target.

Vascular endothelial dysfunction is a key biological process underlying the development of cardiovascular disease and therefore of potential importance as a target for gene-based therapy. Modification of nitric oxide bioavailability through gene therapy is possible in animal studies and of clinical relevance because of the central role for nitric oxide in vascular homeostasis. However, most clinical trials have so far focused on endothelial-related pathways, in particular, vascular endothelial growth factor, to induce angiogenesis, with variable results. The slow progress of the development of gene-therapy targeted at the endothelium relates to a range of complexities of design of therapy including mode of gene delivery. This is usually achieved through the use of viral or non-viral vectors but the best physical and vector methods for delivery of complimentary DNA to the vascular endothelium remains under investigation. More recently there has been emerging interest into other genome-based methods to alter vascular phenotype, in particular, gene-based modification of endothelial progenitor cell function and whether gene function might be modifiable through induced epigenetic changes.