Current Vascular Pharmacology - Volume 14, Issue 2, 2016

Purinergic signalling is involved in the control of vascular tone and remodelling. Endothelial cells release purines and pyrimidines in response to changes in blood flow (evoking shear stress) and hypoxia. They then act on P2Y, P2X and P1 receptors on endothelial cells leading to release of EDRF mediated by nitric oxide and prostaglandins and EDHF, resulting in vasodilatation. The therapeutic potential of purinergic compounds for the treatment of vascular diseases, including hypertension, ischaemia, atherosclerosis, migraine and coronary artery and diabetic vascular disease as well as vasospasm is discussed.

Heart valves are sophisticated cellularised structures that perform a complex series of dynamic functions during each cardiac cycle. The endothelial cells (ECs) that cover both surfaces of the valve, play an important role in ensuring that the valve functions are in an optimal manner. They are also postulated to protect the valve against calcific disease. These functions include a role in embryonic development, regulation of cellular attachment, modulation of the mechanical properties of the valve, prevention of valve interstitial cell differentiation into pathological cell phenotypes and regulation of the valve extracellular matrix. It is believed that valve endothelial cells (VECs) are a specialised population of ECs which have a distinctive range of properties not seen elsewhere in the vasculature. This allows them to function in a unique haemodynamic environment. Each surface of the valve is exposed to vastly different patterns of blood flow and levels of shear stress, resulting in further specialisation of the VECs on the aortic and ventricular surfaces of the valve. This review will examine the role of VECs on either surface of the valve and demonstrate how they contribute to the function and durability of heart valves.

Diabetes mellitus is a major risk factor for the development of cardiovascular disease due to increased vascular inflammatory and oxidative stress favouring atherogenesis. Endothelial dysfunction has received increasing attention as a potential contributor to the pathogenesis of vascular disease in diabetes mellitus. Although the underlying cause of endothelial dysfunction is multifactorial, a key factor is impairment of the bioavailability of nitric oxide (NO). Emerging evidence suggest that upregulation of arginase is of central importance for reduced NO bioavailability due to competition for the substrate L-arginine between arginase and the endothelial form of NO synthase. Arginase is also associated with increased oxidative stress, further impairing NO bioavailability. Upregulation of arginase has been suggested to be a key factor driving endothelial dysfunction in diabetes. The present review describes the regulation of arginase in relation to diabetes and arginase as a potential therapeutic target to improve endothelial function in experimental models and the clinical setting of diabetes mellitus.

Erectile dysfunction (ED) affects approximately half of men during middle age. Erectile dysfunction is often an early symptom of systemic vascular disease, which may precipitate significant cardiac events. The pathophysiology of ED and cardiovascular disease is closely linked. Endothelial dysfunction occurs at an early stage in ED and cardiovascular disease (CVD). In normal conditions, nitric oxide dependent and independent mechanisms regulate penile vascular tone ensuring an appropriate balance of vasoconstriction and vasodilatation. A normal endothelium is responsible for mediating the effect of pro-erectile mediators derived from the endothelium and is critical in normal erectile function. Endothelial dysfunction disrupts the homeostatic mechanisms responsible for regulation of smooth muscle contraction and penile vascular tone. Reduced bioavailability of nitric oxide (NO) occurs as a response to endothelial damage. Phosphodiesterases further degrade levels of cyclic guanosine monophosphate (cGMP) and impair smooth muscle relaxation and erectile function. A number of endothelium derived NO independent mediators of erectile function have been described and are known to contribute to ED in the presence of endothelial damage. This review provides an up to date analysis of the role of the endothelium in ED describing the pathways involved and how these represent current and potential therapeutic targets.

Adipose tissue (AT) is now widely accepted as a key secretary organ, as well as an energy storage depot. It secretes a series of cytokines, hormones and bioactive molecules: adipokines. Adiponectin is an abundant systemic adipokine that uniquely is reduced in obesity and increases on weight loss, is anti-inflammatory, promotes insulin sensitivity and affords cardiometabolic protection. It was considered a true adipokine, in that it is exclusively generated by the adipocytes of the adipose tissue. However, recent evidence points to it being secreted by a range of other organs. This review summarizes the non-adipose sources of adiponectin especially that derived from the endothelium, its vasoprotective role and intracellular signalling pathways. Endothelium derived adiponectin may potentially be a new target for clinical intervention in cardiovascular disease.

This essay focuses on nine important lessons learned during more than thirty years of endothelial research. They include: the danger of hiding behind a word, the confusion generated by abbreviations, the need to define the physiological role of the response studied, the local role of endothelium- dependent responses, the strength of pharmacological analyses, endothelial dysfunction as consequence and cause of disease, the importance of rigorous protocols, the primacy of in vivo studies and the importance of serendipity.

The vascular endothelium plays a pivotal role in regulating vascular homeostasis. Blood flow exerts several mechanical forces on the luminal surface of the Endothelial Cell (EC) including pressure, circumferential stretch, and shear stress. It is widely believed that shear stress plays a central role in regulating EC inflammatory responses and the pathogenesis of atherosclerosis. High shear stress can induce an antiinflammatory status in EC, which is partially mediated by the production of proteins and transcription factors able to suppress different proinflammatory signalling pathways. In this review, we summarise the available evidence regarding the effect of shear stress on vascular EC and smooth muscle cells, the regulation of MAPK and NF-ΚB including the production of different negative regulators of inflammation such as MKP-1 and NRF2, and the production of microRNAs. We also discuss the possible links between shear stress and the development of atherosclerosis.

Endothelium is a site of metabolic activity and has a major reservoir of multipotent stem cells. It plays a vital role in the vascular physiological, pathophysiological and reparative processes. Endothelial functions are significantly altered following hypovolemic shock due to ischemia of the endothelial cells and by reperfusion due to resuscitation with fluids. Activation of endothelial cells leads to release of vasoactive substances (nitric oxide, endothelin, platelet activating factor, prostacyclin, mitochondrial N-formyl peptide), mediators of inflammation (tumor necrosis factor , interleukins, interferons) and thrombosis. Endothelial cell apoptosis is induced following hypovolemic shock due to deprivation of oxygen required by endothelial cell mitochondria; this lack of oxygen initiates an increase in mitochondrial reactive oxygen species (ROS) and release of apoptogenic proteins. The glycocalyx structure of endothelium is compromised which causes an impairment of the protective endothelial barrier resulting in increased permeability and leakage of fluids in to the tissue causing edema. Growth factors such as angiopoetins and vascular endothelial growth factors also contribute towards pathophysiology of hypovolemic shock. Endothelium is extremely active with numerous functions, understanding these functions will provide novel targets to design therapeutic agents for the acute management of hypovolemic shock. Hypovolemic shock also occurs in conditions such as dengue shock syndrome and Ebola hemorrhagic fever, defining the role of endothelium in the pathophysiology of these conditions will provide greater insight regarding the functions of endothelial cells in vascular regulation.

An inverse association between diabetes mellitus (DM) and abdominal aortic aneurysm (AAA) risk have been reported. Apart from a lower AAA prevalence among patients with vs without DM, there are data showing that DM may exert a protective role on aneurysmal growth in patients with small AAAs, thus decreasing the risk of rupture. As atherosclerosis has almost the same risk factors as aneurysms, the decreased AAA prevalence in patients with DM may indicate that atherosclerosis is an associated feature and not a cause of the aneurysms. Alternatively, DM may be associated with factors that influence AAA formation. In this narrative review, we discuss the inverse association between DM and AAA. We also comment on underlying cellular and genetic pathophysiological mechanisms of DM, AAA and atherosclerosis. The effects of drugs, commonly prescribed in DM patients, on AAA development and growth are also considered.

Objective: Liraglutide 3.0 mg daily dose is marketed under the brand name Saxenda and was recently approved by both the Food and Drug Administration (FDA) and the European Medicine Agency (EMA) as adjunct to a comprehensive lifestyle intervention to achieve weight loss. Design: Human studies using liraglutide 3.0 mg daily dose were selected through search based on PubMed listings and the Clinical trials.gov database using the term “liraglutide”. Results: During 56 weeks of treatment, liraglutide 3.0 mg treatment resulted in 5.9-8.0% weight reduction, while the placebo-subtracted weight loss was 3.9-6.0%. The proportion of treated patients with ≥ 5% weight loss was 50-76%, while the placebo-subtracted proportion was 29-46%. Liraglutide 3.0 mg treatment also induced a decrease in waist circumference, serum triglycerides, insulin resistance, blood pressure and an increase in high density lipoprotein-cholesterol (HDL-C). The most common side effects were nausea, hypoglycemia, diarrhea, constipation, vomiting and headache. In the majority of patients liraglutide 3.0 mg was well tolerated. Conclusion: Liraglutide 3.0 mg appears to be an effective adjunct to a comprehensive lifestyle intervention to achieve weight reduction and treat obesity-related comorbidities.

Vascular calcification, both in the coronary and in the peripheral arteries, is associated with increased cardiovascular (CV) risk. However, agents that prevent vascular calcification (e.g. estrogens or calcimimetic agents) might have neutral or detrimental effects on CV events. Moreover, statins and antihypertensive agents do not appear to modify vascular calcification, despite their established benefits on CV disease prevention. On the other hand, recent data suggest that microRNAs play a role in the regulation of vascular calcification. It is therefore possible that modulation of the expression of microRNAs might represent a useful strategy for preventing or delaying the progression of this process.

Cellular function phenotype is regulated by various microRNAs (miRs), including miR-135a. However, how miR-135a is involved in the calcification in senescent vascular smooth muscle cells (VSMCs) is not clear yet. In the present study, we first identified the significantly altered miRNAs in VSMCs, then performed consecutive passage culture of VSMCs and analyzed the expression of miR- 135a and calcification genes in the senescent phase. Next, the effects of the miR-135a inhibition on calcification and calcification genes were analyzed. The luciferase assay was used to validate the target protein of miR-135a. The western blotting was used to determine the effects of miR-135a on Krüppel-like factor 4 (KLF4) and signal transducer and activator of transcription 3 protein (STAT3) expression, as well as the relationship between KLF4 and STAT3. Finally, the quantified cellular calcification was measured to examine the involvement of miR-135a, KLF4 and STAT3 in VSMCs calcification. Our results showed that miR-135a was significantly altered in VSMCs. Cell calcification and calcification genes were greatly altered by miR-135a inhibition. KLF4 was validated as the target RNA of miR-135a. Expression of KLF4 and STAT3 were both significantly decreased by over expressed miR-135a, while the inhibition of miR-135a and KLF4 siRNA both decreased the STAT3 protein levels. Moreover, the inhibition of miR-135a dramatically increased the calcium concentration, but co-treatment with KLF4 or STAT3 siRNA both decreased the calcium concentration. The present study identified miR-135a as a potential osteogenic differentiation suppressor in senescent VSMCs and revealed that KLF4/STAT3 pathway, at least partially, was involved in the mechanism.