Drug treatment of hypertension: focus on vascular health

Hypertension, the most common preventable risk factor for cardiovascular disease and death, is a growing health burden. Serious cardiovascular complications result from target organ damage including cerebrovascular disease, heart failure, ischaemic heart disease and renal failure. While many systems contribute to blood pressure (BP) elevation, the vascular system is particularly important because vascular dysfunction is a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, arterial remodelling, vascular inflammation and increased stiffness. Antihypertensive drugs that influence vascular changes associated with high BP have greater efficacy for reducing cardiovascular risk than drugs that reduce BP, but have little or no effect on the adverse vascular phenotype. Angiotensin converting enzyme ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve endothelial function and prevent vascular remodelling. Calcium channel blockers also improve endothelial function, although to a lesser extent than ACEIs and ARBs. Mineralocorticoid receptor blockers improve endothelial function and reduce arterial stiffness, and have recently become more established as antihypertensive drugs. Lifestyle factors are essential in preventing the adverse vascular changes associated with high BP and reducing associated cardiovascular risk. Clinicians and scientists should incorporate these factors into treatment decisions for patients with high BP, as well as in the development of new antihypertensive drugs that promote vascular health

Vascular Endothelial Growth Factor Concentration in Brain of Rat Treated with Anaerobic Exercises

Anaerobic exercise is a high-intensity exercise that needs quick energy supplies obtained in a very short time. However, this exercise may result in tissue hypoxia which is characterized by the increase of HIF-1α concentration. The presence of HIF-1α will induce the secretion of VEGF and, eventually, trigger angiogenesis. Nevertheless, it is still unclear whether anaerobic exercise will also cause hypoxia in which this condition will increase the concentration of VEGF in brain tissues. The aim of this study was to find out the effect of anaerobic exercise frequency towards VEGF concentration of Wistar rat brain tissues. Brain tissues were taken from rats treated with anaerobic exercise using treadmill. This exercise was given in different frequencies; one time, three times, and seven times a week. The data collected were analyzed using independent t-test. The results of this study showed that anaerobic exercise done once a week could significantly increase VEGF concentration (p < 0.05) if compared with the one in control group (95.21 ± 31.99 v.s. 63.36 ± 11.01 pg/mL). Meanwhile, VEGF concentration of treatment groups given exercise three times a week (47.97 ± 10.68 pg/mL) and seven times a week (40.56 ± 13.98 pg/mL) showed a significant decrease if compared with that of control group (63.36 ± 11.01 pg/mL). Anaerobic exercise affected VEGF concentration as an indicator of angiogenesis in brain tissue of wistar rats

Substrate stiffness and VE-cadherin mechano-transduction coordinate to regulate endothelial monolayer integrity.

The vascular endothelium is subject to diverse mechanical cues that regulate vascular endothelial barrier function. In addition to rigidity sensing through integrin adhesions, mechanical perturbations such as changes in fluid shear stress can also activate force transduction signals at intercellular junctions. This study investigated how extracellular matrix rigidity and intercellular force transduction, activated by vascular endothelial cadherin, coordinate to regulate the integrity of endothelial monolayers. Studies used complementary mechanical measurements of endothelial monolayers grown on patterned substrates of variable stiffness. Specifically perturbing VE-cadherin receptors activated intercellular force transduction signals that increased integrin-dependent cell contractility and disrupted cell-cell and cell-matrix adhesions. Further investigations of the impact of substrate rigidity on force transduction signaling demonstrated how cells integrate extracellular mechanics cues and intercellular force transduction signals, to regulate endothelial integrity and global tissue mechanics. VE-cadherin specific signaling increased focal adhesion remodeling and cell contractility, while sustaining the overall mechanical equilibrium at the mesoscale. Conversely, increased substrate rigidity exacerbates the disruptive effects of intercellular force transduction signals, by increasing heterogeneity in monolayer stress distributions. The results provide new insights into how substrate stiffness and intercellular force transduction coordinate to regulate endothelial monolayer integrity

Dual control of vascular tone and remodelling by ATP released from nerves and endothelial cells

Purinergic signalling is important both in short-term control of vascular tone and in longer-term control of cell proliferation, migration and death involved in vascular remodelling. There is dual control of vascular tone by ATP released from perivascular nerves and by ATP released from endothelial cells in response to changes in blood flow (shear stress) and hypoxia. Both ATP and its breakdown product, adenosine, regulate smooth muscle and endothelial cell proliferation. The involvement of these regulatory mechanisms in pathological conditions, including hypertension, atherosclerosis, restenosis, diabetes and vascular pain, are discussed

Positive and negative regulation of angiogenesis by soluble vascular endothelial growth factor receptor-1

Vascular endothelial growth factor receptor (VEGFR)-1 exists in different forms, derived from alternative splicing of the same gene. In addition to the transmembrane form, endothelial cells produce a soluble VEGFR-1 (sVEGFR-1) isoform, whereas non-endothelial cells produce both sVEGFR-1 and a different soluble molecule, known as soluble fms-like tyrosine kinase (sFlt)1-14. By binding members of the vascular endothelial growth factor (VEGF) family, the soluble forms reduce the amounts of VEGFs available for the interaction with their transmembrane receptors, thereby negatively regulating VEGFR-mediated signaling. In agreement with this activity, high levels of circulating sVEGFR-1 or sFlt1-14 are associated with different pathological conditions involving vascular dysfunction. Moreover, sVEGFR-1 and sFlt1-14 have an additional role in angiogenesis: they are deposited in the endothelial cell and pericyte extracellular matrix, and interact with cell membrane components. Interaction of sVEGFR-1 with α5β1 integrin on endothelial cell membranes regulates vessel growth, triggering a dynamic, pro-angiogenic phenotype. Interaction of sVEGFR-1/sFlt1-14 with cell membrane glycosphingolipids in lipid rafts controls kidney cell morphology and glomerular barrier functions. These cell-matrix contacts represent attractive novel targets for pharmacological intervention in addition to those addressing interactions between VEGFs and their receptors

Microvascular alterations in hypertension and vascular aging

Hypertension and aging are characterized by vascular remodelling and stiffness as well as endothelial dysfunction. Endothelial function declines with age, since aging is associated with senescence of the endothelium due to increased rate of apoptosis and reduced regenerative capacity of the endothelium. Different phenotypes of hypertension have been described in younger and adult subjects with hypertension. In younger patients functional and structural alterations of resistance arteries occur as the earliest vascular alterations which have prognostic significance and may contribute to stiffness of large arteries through wave reflection. In individuals above age of 50 years as well as in subjects with long-lasting elevated blood pressure, vascular changes occur predominantly in conduit arteries which become stiffer. Activation of renin-angiotensin-aldosterone and endothelin systems plays a key role in endothelial dysfunction, vascular remodelling, and aging by inducing reactive oxygen species production, and promoting inflammation and cell growth

T-cadherin deficiency increases vascular vulnerability in T2DM through impaired NO bioactivity.

BACKGROUND: Endothelial dysfunction plays a critical role in the development of type 2 diabetes (T2DM). T-cadherin (T-cad) has gained recognition as a regulator of endothelial cell (EC) function. The present study examined whether T-cad deficiency increases vascular vulnerability in T2DM. METHODS: Vascular segments were isolated from WT or T-cad knockout mice. Endothelial function, total NO accumulation, and the expression of T-cad related proteins were determined. RESULTS: Ach and acidified NaNO2 induced similar vasorelaxation in WT groups. T-cad KO mice exhibited normal response to acidified NaNO2, but manifested markedly reduced response to Ach. NO accumulation was also decreased in T-cad KO group. T-cad expression was reduced in WT mice fed 8 weeks of high fat diet (HFD). Furthermore, exacerbated reduction of vasorelaxation was observed in T-cad KO mice fed 8 weeks of HFD. CONCLUSIONS: In the current study, we provide the first in vivo evidence that T-cadherin deficiency causes endothelial dysfunction in T2DM vascular segments, suggesting the involvement of T-cad deficiency in T2DM pathogenesis

Surface modification of hydrophobic polymers for improvement of endothelial cell-surface interactions

The aim of this study is to improve the interaction of endothelial cells with polymers used in vascular prostheses. Polytetrafluoroethylene (PTFE; Teflon) films were treated by means of nitrogen and oxygen plasmas. Depending on the plasma exposure time, modified PTFE surfaces showed water-contact angles of 15¿58° versus 96° for unmodified PTFE. Electron spectroscopy in chemical analysis (ESCA) measurements revealed incorporation of both nitrogenand oxygen-containing groups into the PTFE surfaces, dependent on the plasma composition and exposure time. In-vitro biological evaluation of unmodified and modified PTFE surfaces showed that human endothelial cells, seeded from 20% human serum-containing culture medium, adhered well on to modified PTFE surfaces, but not on to unmodified films. Adhesion of endothelial cells on to expanded PTFE graft material (Gore-Tex) was also stimulated by plasma treatment of this substrate. On plasma-treated expanded PTFE, the adhering endothelial cells formed a monolayer, which covered the textured surface. The latter observation is important in view of the hemocompatibility of vascular grafts seeded with endothelial cells before implantation

Short-term impact of aged garlic extract on endothelial function in diabetes: A randomized, double-blind, placebo-controlled trial.

Impaired endothelial function portends an increased risk of cardiovascular disease. Vascular oxidative stress and systemic inflammation play a critical role in the pathogenesis and progression of vascular disease. Aged garlic extract (AGE) may improve impaired vascular endothelial function, while decreasing the progression of atherosclerotic plaque. We hypothesized that AGE may improve endothelial function, and in this study, we examined this hypothesis to determine whether this can be achieved over a period of 3 months, measured by the cardio-ankle vascular index (CAVI), by reducing intracellular oxidant stress and stimulating nitric oxide generation in endothelial cells. We conducted a double-blinded placebo controlled, randomized clinical trial to investigate the effects of AGE on CAVI in subjects with type 2 diabetes mellitus. A total of 65 individuals (38 men and 27 women) with a mean age of 58.8±11.1 years were enrolled and randomized to the AGE or placebo group in a double-blind placebo controlled trial. An ANOVA model with treatment as the main effect was used to compare changes in CAVI from baseline to follow-up between groups. The primary objective of this study was reduction in CAVI over a 3-month period. In the AGE group, CAVI was reduced on average by 0.71±1.27 vs. a mean reduction of 0.13±0.94 in the placebo group (P=0.04). On the whole, this study demonstrates that AGE has a positive impact on endothelial function in patients with T2DM and may play a role in the primary prevention of cardiovascular disease

Role of noncoding RNA in vascular remodelling

Purpose of review: Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are becoming fundamentally important in the pathophysiology relating to injury-induced vascular remodelling. We highlight recent studies that demonstrate the involvement of ncRNAs in vein graft disease, in in-stent restenosis and in pulmonary arterial hypertension, with a particular focus on endothelial cell and vascular smooth muscle cell function. We also briefly discuss the emerging role of exosomal-derived ncRNAs and how this mechanism impacts on vascular function. Recent findings: ncRNAs have been described as novel regulators in the pathophysiology of vascular injury, inflammation, and vessel wall remodelling. In particular, several studies have demonstrated that manipulation of miRNAs can reduce the burden of pathological vascular remodelling. Such studies have also shown that exosomal miRNA-mediated, cell-to-cell communication between endothelial cells and vascular smooth muscle cells is critical in the disease process. In addition to miRNAs, lncRNAs are emerging as regulators of vascular function in health and disease. Although lncRNAs are complex in both their sheer numbers and mechanisms of action, identifying their contribution to vascular disease is essential. Summary: Given the important roles of ncRNAs in vascular injury and remodelling together will their capacity for cell-to-cell communication, manipulating ncRNA might provide novel therapeutic interventions