The endothelium is a crucial regulator of vascular physiology, producing in healthy conditions several substances with a potent antiatherosclerotic properties. Accordingly, the presence of ...endothelial dysfunction is associated with subclinical atherosclerosis and with an increased future risk of cardiovascular events. A large body of evidence supports the fundamental role of nitric oxide (NO) as the main endothelium‐derived relaxing factor. However, in the presence of pathological conditions, such as hypertension, endothelial cells, in response to a number of agents and physical stimuli, become also a source of endothelium‐derived contracting factors (EDCFs), including endothelins and angiotensin II and particularly cyclooxygenase‐derived prostanoids and superoxide anions. These latter were at first identified as responsible for impaired endothelium‐dependent vasodilation in patients with essential hypertension. However, cyclooxygenase‐dependent EDCFs production is characteristic of the aging process, and essential hypertension seems to only anticipate the phenomenon. It is worth noting that both in aging and hypertension EDCF production is associated with a parallel decrease in NO availability, suggesting that this substance could be oxygen free radicals themselves. Accordingly, in hypertension both indomethacin, a cyclooxygenase inhibitor, and vitamin C, an antioxidant, increase the vasodilation to acetylcholine by restoring NO availability. In conclusion, hypertension is characterized by a decline in endothelial function, associated with a progressive decrease in NO bioavailability and increase in the production of EDCF. The mechanisms that regulate the balance between NO and EDCF, and the processes transforming the endothelium from a protective organ to a source of vasoconstrictor, proaggregatory and promitogenic mediators remain to be determined.
British Journal of Pharmacology (2009) 157, 527–536; doi:10.1111/j.1476‐5381.2009.00240.x
This article is part of a themed section on Endothelium in Pharmacology. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
Ageing is a major risk factor for cardiovascular disease, not only because there is a process of vascular ageing per se but also because ageing increases the time of exposure to other cardiovascular ...risk factors. Endothelial dysfunction is now
considered an early and important mechanism that predisposes to atherothrombotic damage and thus contributes to the occurrence
of cardiovascular events. The normal endothelium exerts a major vascular-protecting role by secreting substances, the most
important of which is nitric oxide (NO). In disease conditions (such as the presence of cardiovascular risk factors), activation
of endothelial cells can lead to the production and release of contracting factors, which counteract the beneficial effects
of NO, and reactive oxygen species (ROS), which cause NO breakdown. Besides the opposite effects on vascular tone, NO and
endothelium-derived contracting factors also respectively inhibit and activate several other mechanisms that are involved
in the pathogenesis of atherothrombosis. Moreover, endothelial dysfunction is associated with vascular subclinical damage
and, importantly, an increasing body of evidence strongly suggests that it might be an independent predictor for the risk
of future cardiovascular events. Like the other traditional risk factors, ageing has been demonstrated to be associated with
progressive impairment of endothelial function, in both conduit arteries and resistance vessels, mainly because of an increased
production of ROS. Therefore, it is conceivable that endothelial dysfunction plays a major role in predisposing to age-related
increased cardiovascular risk in the elderly.
Renal artery stenosis (RAS) causes renovascular hypertension and renal damage, which may result from tissue inflammation. We have previously shown that the kidney in RAS exhibits increased expression ...of monocyte chemoattractant protein (MCP)-1, but its contribution to renal injury remained unknown. This study tested the hypothesis that MCP-1 contributes to renal injury and dysfunction in the stenotic kidney.
Kidney hemodynamics, function, and endothelial function were quantified in pigs after 10 weeks of experimental RAS (n = 7), RAS supplemented with the MCP-1 inhibitor bindarit (RAS + bindarit, 50 mg/kg/day orally, n = 6), and normal controls (n = 8). Renal inflammation was assessed by the immunoreactivity of MCP-1, its receptor chemotactic cytokine receptor 2, and NFkappaB, and oxidative stress by nicotinamide adenine dinucleotide phosphate-oxidase expression and in-situ superoxide production. Renal microvascular density was evaluated by micro-CT and fibrosis by trichrome staining, collagen-I immunostaining, and hydroxyproline content.
After 10 weeks of RAS, blood pressure was similarly elevated in RAS and RAS + bindarit. Compared with normal controls, stenotic RAS kidneys had decreased renal blood flow (5.4 +/- 1.6 vs. 11.4 +/- 1.0 ml/min/kg, P < 0.05) and glomerular filtration rate and impaired endothelial function, which were significantly improved in bindarit-treated RAS pigs (to 8.4 +/- 0.8 ml/min/kg, P < 0.05 vs. RAS). Furthermore, bindarit markedly decreased tubulointerstitial (but not vascular) oxidative stress, inflammation, and fibrosis, and slightly increased renal microvascular density. The impaired renovascular endothelial function, increased oxidative-stress, and fibrosis in the contralateral kidney were also improved by bindarit.
MCP-1 contributes to functional and structural impairment in the kidney in RAS, mainly in the tubulointerstitial compartment. Its inhibition confers renoprotective effects by blunting renal inflammation and thereby preserving the kidney in chronic RAS.
Patients with hypertension and chronic kidney disease are at risk for cardiovascular diseases, possibly related to inflammation. Statins have beneficial anti-inflammatory effects on vascular ...structure regardless of cholesterol reduction. It was hypothesized that alterations in myocardial microvascular structure in swine renovascular hypertension (RVH) would be improved by simvastatin treatment. Three groups of pigs were studied after 12 wk: normal (n = 7), RVH (n = 7), or RVH+simvastatin (RVH+S; 80 mg/d; n = 6). Left ventricular muscle mass and myocardial perfusion were determined in vivo using electron beam computed tomography, and myocardial samples then were scanned ex vivo using micro-computed tomography for measurement of the spatial density of myocardial microvessels (80 to 500 microm) in situ. Capillary density and myocardial expression of inflammatory and growth factors were determined in myocardial tissue. The effects of simvastatin on inflammation-induced tube formation were evaluated in vitro in human umbilical vein endothelial cells that were exposed to TNF-alpha. RVH and RVH+S had similarly increased arterial pressure and serum creatinine. However, left ventricular hypertrophy was prevented by simvastatin, and myocardial perfusion was increased. Compared with normal, RVH showed increased spatial density of microvessels (169.6 +/- 21 versus 107.7 +/- 15.2 vessels/cm(2); P < 0.05), which was decreased in RVH+S (72.5 +/- 14.9 vessels/cm(2)), whereas capillary density remained similar to normal. RVH also increased myocardial expression of inflammatory and growth factors, which were reversed by simvastatin. Furthermore, simvastatin attenuated TNF-alpha-induced angiogenesis in vitro. Simvastatin prevents myocardial microvascular remodeling and hypertrophy in experimental RVH independent of lipid lowering. This protective effect is partly mediated by blunted expression as well as angiogenic activity of inflammatory cytokines.
The time-dependent effects of mild hypothyroidism on endothelial function were assessed in rat mesenteric arteries. Male Wistar rats were treated with methimazole (MMI; 0.003%) or placebo up to 16 ...wk. Endothelial function of mesenteric small arteries was assessed by pressurized myograph. MMI-treated animals displayed a decrease in serum thyroid hormones, an increment of plasma TSH and inflammatory cytokines, and a blunted vascular relaxation to acetylcholine, as compared with controls. Endothelial dysfunction resulted from a reduced nitric oxide (NO) availability caused by oxidative excess. Vascular-inducible NO synthase (iNOS) expression was up-regulated. S-methylisothiourea (an iNOS inhibitor) normalized endothelium-dependent relaxations and restored NO availability in arteries from 8-wk MMI-animals and partly ameliorated these alterations in 16-wk MMI rats. Similar results were obtained when MMI-induced hypothyroidism was prevented by T4 replacement. Among controls, an impaired NO availability, secondary to oxidative excess, occurred at 16 wk, and it was less pronounced than in age-matched MMI animals. Both endothelial dysfunction and oxidant excess secondary to aging were prevented by apocynin (nicotinamide adenine dinucleotide phosphate oxidase inhibitor). Mesenteric superoxide production was reduced by S-methylisothiourea and T4 replacement in MMI animals and abolished by apocynin in controls (dihydroethidium staining). MMI-induced mild hypothyroidism is associated with endothelial dysfunction caused by a reduced NO availability, secondary to oxidative excess. It is suggested that in this animal model, characterized by TSH elevation and low-grade inflammation, an increased expression and function of iNOS, resulting in superoxide generation, accounts for an impaired NO availability.
In methimazole-induced mild hypothyroid rats, low-grade inflammation and an increased inducible nitric oxide synthase enhance vascular oxidative stress generation, leading to reduced nitric oxide availability.
The purpose of this work was to compare the effects of hypertension and hypercholesterolemia on carotid endothelial function, structure, and vasa vasorum density. Seventeen pigs were randomized to a ...12-week normal diet without (n=5), or with renovascular hypertension (HT; n=6), or to a high cholesterol diet (HC; n=6). Carotid arteries were studied by organ chambers (endothelial function) and microcomputed tomography (vasa vasorum), and tissue was processed for Sirius red staining and immunoblotting (vascular endothelium growth factor, endostatin, matrix metalloproteinase-9, and matrix metalloproteinase-2). HC and HT showed reduced vasodilation to acetylcholine as compared with controls, but HT also had a lower response to sodium nitroprusside. In addition, HT showed a higher content of organized collagen fibers and increased intima-media thickness. Vasa vasorum density was increased in HC but not in HT. Both HT and HC showed a proangiogenetic biochemical milieu (higher vascular endothelium growth factor, matrix metalloproteinases, and lower endostatin), but this was more pronounced in HC. Both hypertension and hypercholesterolemia induce endothelial dysfunction in the carotid artery. However, hypertension is also associated with greater fibrosis and vascular wall thickening, which might impair endothelium-independent vasorelaxation and vasa vasorum growth. Hypercholesterolemia is, in turn, associated with vasa vasorum neovascularization. These data suggest that carotid atherosclerosis can evolve through different mechanisms in relation to different risk factors.
The effects of chronic supplementation with antioxidant vitamins on angiogenesis are controversial. The aim of the present study was to evaluate in kidneys of normal pigs the effect of chronic ...supplementation with vitamins E and C, at doses that are effective in reducing oxidative stress and attenuating angiogenesis under pathological conditions. Domestic pigs were randomized to receive a 12-wk normal diet without (n = 6) or with antioxidant vitamins supplementation (1g/day vitamin C, 100 IU.kg(-1).day(-1) vitamin E; n = 6). Electron beam computed tomography (CT) was used to evaluate renal cortical vascular function in vivo, and micro-CT was to assess the spatial density and average diameter of cortical microvessels (diameter <500 microm) ex vivo. Oxidative stress and expressions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1alpha were evaluated in renal tissue. The effects of increasing concentrations of the same vitamins on redox status and angiogenesis were also evaluated in human umbilical vascular endothelial cells (HUVEC). Compared with normal pigs, the density of cortical transmural microvessels was significantly greater in vitamin-supplemented pigs (149.0 +/- 11.7 vs. 333.8 +/- 48.1 vessel/cm(2), P < 0.05), whereas the cortical perfusion response to ACh was impaired. This was accompanied by a significant increase in tissue oxidative stress and levels of VEGF and HIF-1alpha. A low dose of antioxidant decreased, whereas a high dose increased, HUVEC oxidative stress and angiogenesis, which was partly mediated by hydrogen peroxide. Antioxidant vitamin supplementation can increase tissue oxidative redox and microvascular proliferation in the normal kidney, probably due to a biphasic effect that depends on basal redox balance.
Strategies for identifying normotensive patients with acute symptomatic PE at high risk of PE-related complications remain to be defined.
This prospective cohort study aimed to determine the role of ...plasma lactate levels in the risk assessment of normotensive patients with acute PE. Outcomes assessed over the 7 days after the diagnosis of PE included PE-related mortality and haemodynamic collapse, defined as need for cardiopulmonary resuscitation, systolic blood pressure <90 mm Hg for at least 15 min, need for catecholamine administration, or need for mechanical ventilation.
Between December 2012 and January 2014, the study enrolled 496 normotensive outpatients with acute symptomatic PE. PE-related complications occurred in 20 (4.0%; 95% CI 2.5% to 6.2%) of the 496 patients. These patients had higher baseline lactate levels (median 2.66 mmol/L; IQR 1.56-5.96 mmol/L) than patients without complications (1.20 mmol/L; IQR 1.20-2.00 mmol/L) (p<0.001). Overall, 135 patients (27.2%) had plasma lactate ≥2 mmol/L. Fourteen (10.4%) of them had PE-related complications versus 6 of 361 patients with low lactate (negative predictive value 98.3%; p<0.001). Patients with elevated plasma lactate had an increased rate of PE-related complications (adjusted OR 5.3; 95% CI 1.9 to 14.4; p=0.001) compared with those with low lactate. The combination of elevated plasma lactate with markers of right ventricular dysfunction (by echocardiogram) and myocardial injury (by cardiac troponin) was a particularly useful prognostic indicator (positive predictive value 17.9%; 95% CI 6.1% to 36.9%).
Plasma lactate represents a powerful predictor of short-term PE-related complications and may provide guidance for decision-making in PE care.
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