Endothelial C-type natriuretic peptide maintains vascular homeostasis

PMCID: PMC4151218Wellcome Trust (084449/Z/07/Z and 078496/Z/05/Z

Experimental Benefits of Sex Hormones on Vascular Function and the Outcome of Hormone Therapy in Cardiovascular Disease

Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Experimental data have shown beneficial vascular effects of estrogen including stimulation of endothelium-dependent nitric oxide, prostacyclin and hyperpolarizing factor-mediated vascular relaxation. However, the experimental evidence did not translate into vascular benefits of hormone replacement therapy (HRT) in postmenopausal women, and HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events with HRT. The lack of vascular benefits of HRT could be related to the hormone used, the vascular estrogen receptor (ER), and the subject’s age and preexisting cardiovascular condition. Natural and phytoestrogens in small doses may be more beneficial than synthetic estrogen. Specific estrogen receptor modulators (SERMs) could maximize the vascular benefits, with little side effects on breast cancer. Transdermal estrogens avoid the first-pass liver metabolism associated with the oral route. Postmenopausal decrease and genetic polymorphism in vascular ER and post-receptor signaling mechanisms could also modify the effects of HRT. Variants of cytosolic/nuclear ER mediate transcriptional genomic effects that stimulate endothelial cell growth, but inhibit vascular smooth muscle (VSM) proliferation. Also, plasma membrane ERs trigger not only non-genomic stimulation of endothelium-dependent vascular relaxation, but also inhibition of [Ca2+]i, protein kinase C and Rho kinase-dependent VSM contraction. HRT could also be more effective in the perimenopausal period than in older postmenopausal women, and may prevent the development, while worsening preexisting CVD. Lastly, progesterone may modify the vascular effects of estrogen, and modulators of estrogen/testosterone ratio could provide alternative HRT combinations. Thus, the type, dose, route of administration and the timing/duration of HRT should be customized depending on the subject’s age and preexisting cardiovascular condition, and thereby make it possible to translate the beneficial vascular effects of sex hormones to the outcome of HRT in postmenopausal CVD

Vasorelaxant Effect of Trachelospermi caulis Extract on Rat Mesenteric Resistance Arteries

Background: Trachelospermi caulis (T. caulis) has been used as a traditional herbal medicine in Asian countries. Although it is well known that T. caulis has beneficial effects, no sufficient research data are available on the cardiovascular effect of T. caulis. We investigated whether T. caulis extract has vascular effects in rat resistance arteries in this study. Methods: To examine whether T. caulis extract affects vascular reactivity, we measured isometric tension of rat mesenteric resistance arteries using a multi-wire myograph system. T. caulis extract was administered after arteries were pre-contracted with high K+ (70 mM) or phenylephrine (5 µM). Vanillin, a single active component of T. caulis, was used to treat mesenteric arteries. Results: T. caulis extract caused vascular relaxation in a concentration-dependent manner, which was endothelium-independent. To further identify the mechanism, we incubated the arteries in Ca2+-free solution containing high K+, followed by a cumulative administration of CaCl2 (0.01-2.0 mM) with or without T. caulis extract (250 µg/mL). The treatment of T. caulis extract decreased contractile responses induced by the addition of Ca2+, which suggested that the extracellular Ca2+ influx was inhibited by the T. caulis extract. Moreover, an active compound of T. caulis extract, vanillin, also induced vasodilation in mesenteric resistance arteries. Conclusion: T. caulis extract and its active compound, vanillin, concentration-dependently induced vascular relaxation in mesenteric resistance arteries. These results suggest that the administration of T. caulis extract could help decrease blood pressure.ope

Resistance artery function in diabetes and hyperglycaemia

Diabetes mellitus is associated with an increased risk of microvascular and macrovascular complications, such as retinopathy, nephropathy, neuropathy and atherosclerosis, which account for the increased morbidity and mortality associated with this disease. There is considerable evidence that these complications are the result of vascular dysfunction, which is closely related to poor glycaemic control. This thesis studied the hypothesis that the vascular abnormalities in diabetes are the consequence of exposure to elevated blood glucose concentrations.To date the majority of studies of vascular function in diabetes have been performed using animal models. However, results from such studies have produced conflicting results and are difficult to relate to the human condition. Therefore, it would be advantageous if vascular function could be studied in vessels isolated from a human source. Due to the irregular and unpredictable nature of obtaining human vessels it was first necessary to develop protocols using animal vessels. Vessel structure was studied using a combination of histological and immunological techniques and this was complemented by functional studies using small vessel myography. Preliminary data demonstrated that storing vessels in a physiological salt solution at 4°C did not alter endothelial or vascular smooth muscle cell function and therefore human vessels could be stored for subsequent functional analysis in the knowledge that this does not adversely affect vascular function. Exposure of rat mesenteric resistance arteries to elevated glucose had no adverse effect on endothelium-dependent relaxation. However, a selective attenuation of endothelin-1 (ET-l)-induced contraction was demonstrated, perhaps indicating alterations in ET-1 receptors.Relatively few studies have investigated vascular function in human subcutaneous resistance arteries, hence it was necessary to develop techniques to characterise these vessels. This investigation demonstrated the existence of three distinct vessel types, large and small resistance arteries and veins, which can be distinguished on the basis of physical appearance, differences in response to transmural stretch and functional reactivity. Furthermore, endothelium-dependent relaxation in human subcutaneous resistance arteries was shown to be predominately mediated by an endotheliumderived hyperpolarising factor (EDHF), with little or no contribution from nitric oxide (NO) or prostacyclin (PGI2). Functional investigations in resistance arteries isolated from Type 1 and Type 2 diabetic patients demonstrated unaltered endothelium-dependent and endothelium-independent relaxation. However, there was a selective alteration in contractile function which was related to the type of diabetes.In conclusion, this study has shown that although diabetes is associated with changes in contractile function there was no evidence of impaired endothelial-dependent relaxation. The changes seen in vessels from diabetic patients did not mimic those produced by acute exposure to elevated concentrations of glucose. This suggests that if the vascular alterations observed in diabetes are due to exposure to high glucose concentrations in vivo, prolonged exposure (or factors not present in vitro) are required for abnormalities to develop

Endothelial dysfunction in small arteries and early signs of atherosclerosis in ApoE knockout rats

Endothelial dysfunction is recognized as a major contributor to atherosclerosis and has been suggested to be evident far before plaque formation. Endothelial dysfunction in small resistance arteries has been suggested to initiate long before changes in conduit arteries. In this study, we address early changes in endothelial function of atherosclerosis prone rats. Male ApoE knockout (KO) rats (11- to 13-weeks-old) were subjected to either a Western or standard diet. The diet intervention continued for a period of 20-24 weeks. Endothelial function of pulmonary and mesenteric arteries was examined in vitro using an isometric myograph. We found that Western diet decreased the contribution of cyclooxygenase (COX) to control the vascular tone of both pulmonary and mesenteric arteries. These changes were associated with early stage atherosclerosis and elevated level of plasma total cholesterol, LDL and triglyceride in ApoE KO rats. Chondroid-transformed smooth muscle cells, calcifications, macrophages accumulation and foam cells were also observed in the aortic arch from ApoE KO rats fed Western diet. The ApoE KO rats are a new model to study endothelial dysfunction during the earlier stages of atherosclerosis and could help us improve preclinical drug development.publishedVersio

The Brain and Beyond: Maternal and Fetal Targets of Chronic Alcohol Exposure in Pregnancy

Fetal alcohol spectrum disorders (FASD) persists as significant a public health threat partly due to enmeshment of drinking culture in modern society and partly because of the inherent complexity of alcohol-mediated pathogenesis. Discernment of FASD pathogenesis remains warranted because of the persistence of this threat coupled with extremely limited treatment options for affected patients. In the following studies (Chapters 2 & 3) we used classic approaches to describe a potential mechanism for alcohol-mediated pathogenesis in an atypical focal point of FASD investigation: the maternal uterine artery. The latter part of this work (Chapters 5 & 6) applied advanced technologies (HPLC, next-gen RNA sequencing) to identify new foci in a classic FASD target: the fetal brain. All studies were completed using a well characterized in vivo model of chronic binge prenatal alcohol exposure with clinical relevance. In the uterine artery, alcohol impaired the myogenic response and endothelial-mediated vasodilation, and dysregulation of the nitric oxide (NO) pathway and the enzyme responsible for NO synthesis (eNOS) were presented as susceptible candidates for this dysfunction. Brain studies described here bolster support for pursuing investigation of how excitatory amino acid imbalances influence neurotoxicity, expressly in the developing cerebellum and hippocampus. Transcriptome analysis also identified new hippocampal genes and canonical pathways of investigational interest based on their previous linkage to alcohol and FASD-adjacent pathology but were not tied to FASD contextually to FASD until now. Ultimately, we affirmed that alcohol use during pregnancy is unsafe and poses significant health risks not only to fetal development but to maternal physiology essential for sustaining this development

Pathophysiology of the Adult Respiratory Distress Syndrome and Multi System Organ Failure.

Pulmonary dysfunction in patients with the adult respiratory distress syndrome (ARDS) is nearly always associated with damage to other organs, although such damage may not be clinically apparent. When non-pulmonary in origin ARDS should be considered as an element of multi system organ failure (MSOF). Most patients with MSOF do not die from hypoxemia. Major trauma is nearly always associated with some pulmonary dysfunction, although often subclinical. Medical conditions such as septicaemia, trauma, pancreatitis or burns cause severe inflammatory cascade activation (SICA), which is the most likely cause of MSOF. Oxygen metabolism is central to the development of SICA. Once established SICA causes redistribution of blood flow to and within vital organs. Organs needing a high oxygen delivery (e.g. heart or brain) are deprived of blood by the relatively high flow in less dependant organs (e.g. skin, kidney, or splanchnic bed). In this condition, blood flow is redistributed, producing a relative ischemia and reduction in the production of ATP. This ischemia promotes the formation of super oxides by xanthine oxidase, causing further tissue damage. Ultrastructure studies show that leucocytes aggregate in the lungs, liver and spleen and tissue damage is greatest in these organs. But, even when there is little leucocyte aggregation in the lungs, considerable tissue damage is observed. Leucocytes can be induced to aggregate in the lungs without causing tissue damage. Leucocytes do not aggregate in significant numbers in the heart, kidneys or muscle. Leucocytes are therefore important in the inflammatory cascade of MSOF but not essential. Although there are many biochemical mediators of MSOF, the choke point enzyme phospholipase is the most important and its inhibition may be important in treating the condition

Omega-3 Fatty Acids in Arterial Hypertension: Is There Any Good News?

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including alpha-linolenic acid (ALA) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are “essential” fatty acids mainly obtained from diet sources comprising plant oils, marine blue fish, and commercially available fish oil supplements. Many epidemiological and retrospective studies suggested that ω-3 PUFA consumption decreases the risk of cardiovascular disease, but results of early intervention trials have not consistently confirmed this effect. In recent years, some large-scale randomized controlled trials have shed new light on the potential role of ω-3 PUFAs, particularly high-dose EPA-only formulations, in cardiovascular prevention, making them an attractive tool for the treatment of “residual” cardiovascular risk. ω-3 PUFAs' beneficial effects on cardiovascular outcomes go far beyond the reduction in triglyceride levels and are thought to be mediated by their broadly documented “pleiotropic” actions, most of which are directed to vascular protection. A considerable number of clinical studies and meta-analyses suggest the beneficial effects of ω-3 PUFAs in the regulation of blood pressure in hypertensive and normotensive subjects. These effects occur mostly through regulation of the vascular tone that could be mediated by both endothelium-dependent and independent mechanisms. In this narrative review, we summarize the results of both experimental and clinical studies that evaluated the effect of ω-3 PUFAs on blood pressure, highlighting the mechanisms of their action on the vascular system and their possible impact on hypertension, hypertension-related vascular damage, and, ultimately, cardiovascular outcomes