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Pathogenic mutations in the Gjb2 and Gjb6 genes, encoding connexin 26 (Cx26) and connexin 30 (Cx30), respectively, have been linked to the most frequent monogenic hearing impairment, nonsyndromic hearing loss, and deafness DFNB1. It is known that Cx26 plays an important role in auditory development, while the role of Cx30 in hearing remains controversial. Previous studies found that partial deletion of Cx26 can accelerate age-related hearing loss (ARHL), a multifactorial complex disorder, with both environmental and genetic factors contributing to the etiology of the disease. Here, we investigated the role of Cx30 in cochlear-aging processes using a transgenic mouse model with total deletion of Cx30 (Cx30 delta delta mice), in which Cx30 was removed without perturbing the surrounding sequences. We show that these mice are affected by exacerbated ARHL, with increased morphological cochlear damage, oxidative stress, inflammation, and vascular dysfunctions. Overall, our data demonstrate that Cx30 deletion can be considered a genetic risk factor for ARHL, making cochlear structures more susceptible to aging processes.

We have investigated if EWH could counteract or prevent cardiovascular damage induced by high level of Cd exposure in rats. Male Wistar rats were treated for 14 days with: (A) Untreated - intraperitoneal (i.p.) injections of distilled water and tap water by gavage; (B) Cd − 1 mg/kg of bw/day of CdCl2 (i.p.) and tap water by gavage; (C) EWH – distilled water (i.p.) and 1 mg/kg/day of EWH by gavage; (D) CdEWH – both treatments. EWH prevented the increase on systolic blood pressure, vascular dysfunction, and inflammation after Cd exposure; prevent the activation of cyclooxygenase (COX)-2 and its derived contractile protanoids, inhibits angiotensin II by the reduction of ACE activity and prevents the increased oxidative stress mainly mediated by NADPH oxidase. Multifunctional EWH could be considered as a natural alternative therapy to counteract the deleterious effects caused by high level of Cd exposure.

Background: Despite evolution in decompression algorithms, decompression illness is still an issue nowadays. Reducing vascular gas emboli (VGE) production or preserving endothelial function by other means such as diving preconditioning is of great interest. Several methods have been tried, either mechanical, cardiovascular, desaturation aimed or biochemical, with encouraging results. In this study, we tested mini trampoline (MT) as a preconditioning strategy. Methods: In total, eight (five females, three males; mean age 36 ± 16 years; body mass index 27.5 ± 7.1 kg/m2) healthy, non-smoking, divers participated. Each diver performed two standardized air dives 1 week apart with and without preconditioning, which consisted of ±2 min of MT jumping. All dives were carried out in a pool (NEMO 33, Brussels, Belgium) at a depth of 25 m for 25 min. VGE counting 30 and 60 min post-dive was recorded by echocardiography together with an assessment of endothelial function by flow-mediated dilation (FMD). Results: VGE were significantly reduced after MT (control: 3.1 ± 4.9 VGE per heartbeat vs. MT: 0.6 ± 1.1 VGE per heartbeat, p = 0.031). Post-dive FMD exhibited a significant decrease in the absence of preconditioning (92.9% ± 7.4 of pre-dive values, p = 0.03), as already described. MT preconditioning prevented this FMD decrease (103.3% ± 7.1 of pre-dive values, p = 0.30). FMD difference is significant (p = 0.03). Conclusions: In our experience, MT seems to be a very good preconditioning method to reduce VGE and endothelial changes. It may become the easiest, cheapest and more efficient preconditioning for SCUBA diving., info:eu-repo/semantics/published

The prevalence of mild cognitive impairment increases with age and is further exacerbated by chronic kidney disease (CKD). CKD is associated with (1) mild cognitive impairment, (2) impaired endothelial function, (3) impaired blood-brain barrier, (4) increased cerebral microhemorrhage burden, (5) increased cerebral blood flow (CBF), (6) impaired cerebral autoregulation, (7) impaired cerebrovascular reactivity, and (8) increased arterial stiffness. We report preliminary findings from our group that demonstrate altered cerebrovascular reactivity in a mouse model of CKD-associated vascular calcification. The CBF of CKD mice increased more quickly in response to hypercapnia (p < 0.05) but then decreased prematurely during hypercapnia challenge (p < 0.05). Together, these results indicate that altered kidney function can lead to alterations in the cerebral microvasculature, and hence brain health.

Changes in cellular Ca2+ levels have major influences on vascular function and blood pressure regulation. Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) orchestrate vascular activity in distinct ways, often involving highly-specific fluctuations in Ca2+ signaling. Aging is a major risk factor for cardiovascular diseases, but the impact of aging per se on vascular Ca2+ signaling has received insufficient attention. We reviewed the literature for age-related changes in Ca2+ signaling in relation to vascular structure and function. Vascular tone dysregulation in several vascular beds has been linked to abnormal expression or activity of SMC voltage-gated Ca2+ channels, Ca2+-activated K+ channels or TRPC6 channels. Some of these effects were linked to altered caveolae density, microRNA expression, or 20-HETE abundance. Intracellular store Ca2+ handling was suppressed in aging mainly via reduced expression of intracellular Ca2+ release channels, and Ca2+ reuptake or efflux pumps. An increase in mitochondrial Ca2+ uptake, leading to oxidative stress, could also play a role in SMC hypercontractility and structural remodeling in aging. In ECs, aging entailed diverse effects on spontaneous and evoked Ca2+ transients, as well as structural changes at the EC-SMC interface. The concerted effects of altered Ca2+ signaling on myogenic tone, endothelium-dependent vasodilatation, and vascular structure are likely to contribute to blood pressure dysregulation and blood flow distribution deficits in critical organs. With the rise in the world aging population, future studies should be directed at solving specific aging-induced Ca2+ signaling deficits to combat the imminent accelerated vascular aging and increased risk of cardiovascular diseases.

This dissertation investigates biological causes of depression. Depression is a common mental health problem. However, the mechanisms that could contribute to depression are not fully understood, possibly due to the heterogeneous nature of depression, including differences across age groups. The mechanisms involved in late-life depression might differ from those in early life, and may include vascular dysfunction, neurodegeneration and hyperglycaemia. This dissertation, that includes data of thousands of individuals, shows that microvascular dysfunction and hyperglycaemia are associated with an increased risk of developing depressive symptoms. Successful cardiovascular- and metabolic risk management may not only reduce the risk of cardiovascular diseases but possibly also the risk of depression. In other words, what is good for the heart is good for the brain!

Changes in cellular Ca2+ levels have major influences on vascular function and blood pressure regulation. Vascular smooth muscle cells (SMCs) and endothelial cells (ECs) orchestrate vascular activity in distinct ways, often involving highly-specific fluctuations in Ca2+ signaling. Aging is a major risk factor for cardiovascular diseases, but the impact of aging per se on vascular Ca2+ signaling has received insufficient attention. We reviewed the literature for age-related changes in Ca2+ signaling in relation to vascular structure and function. Vascular tone dysregulation in several vascular beds has been linked to abnormal expression or activity of SMC voltage-gated Ca2+ channels, Ca2+-activated K+ channels or TRPC6 channels. Some of these effects were linked to altered caveolae density, microRNA expression, or 20-HETE abundance. Intracellular store Ca2+ handling was suppressed in aging mainly via reduced expression of intracellular Ca2+ release channels, and Ca2+ reuptake or efflux pumps. An increase in mitochondrial Ca2+ uptake, leading to oxidative stress, could also play a role in SMC hypercontractility and structural remodeling in aging. In ECs, aging entailed diverse effects on spontaneous and evoked Ca2+ transients, as well as structural changes at the EC-SMC interface. The concerted effects of altered Ca2+ signaling on myogenic tone, endothelium-dependent vasodilatation, and vascular structure are likely to contribute to blood pressure dysregulation and blood flow distribution deficits in critical organs. With the rise in the world aging population, future studies should be directed at solving specific aging-induced Ca2+ signaling deficits to combat the imminent accelerated vascular aging and increased risk of cardiovascular diseases.

Pathogenic mutations in the non-syndromic hearing loss and deafness 1 (DFNB1) locus are the primary cause of monogenic inheritance for prelingual hearing loss. To unravel molecular pathways involved in etiopathology and look for early degeneration biomarkers, we used a system biology approach to analyze Cx30−/− mice at an early cochlear post-natal developmental stage. These mice are a DFNB1 mouse model with severely reduced expression levels of two connexins in the inner ear, Cx30, and Cx26. Integrated analysis of miRNA and mRNA expression profiles in the cochleae of Cx30−/− mice at post-natal day 5 revealed the overexpression of five miRNAs (miR-34c, miR-29b, miR-29c, miR-141, and miR-181a) linked to apoptosis, oxidative stress, and cochlear degeneration, which have Sirt1 as a common target of transcriptional and/or post-transcriptional regulation. In young adult Cx30−/− mice (3 months of age), these alterations culminated with blood barrier disruption in the Stria vascularis (SV), which is known to have the highest aerobic metabolic rate of all cochlear structures and whose microvascular alterations contribute to age-related degeneration and progressive decline of auditory function. Our experimental validation of selected targets links hearing acquisition failure in Cx30−/− mice, early oxidative stress, and metabolic dysregulation to the activation of the Sirt1–p53 axis. This is the first integrated analysis of miRNA and mRNA in the cochlea of the Cx30−/− mouse model, providing evidence that connexin downregulation determines a miRNA-mediated response which leads to chronic exhaustion of cochlear antioxidant defense mechanisms and consequent SV dysfunction. Our analyses support the notion that connexin dysfunction intervenes early on during development, causing vascular damage later on in life. This study identifies also early miRNA-mediated biomarkers of hearing impairment, either inherited or age related.

Background and purpose: Migraine is recognized as a vascular risk factor, especially in women. Presumably, migraine, stroke and cardiovascular events share pathophysiological mechanisms. Self-reported cold extremities were investigated as a marker for vascular dysfunction in migraine. Secondly, it was hypothesized that suffering from cold extremities affects sleep quality, possibly exacerbating migraine attack frequency. Methods: In this case–control study, a random sample of 1084 migraine patients and 348 controls (aged 22–65 years) from the LUMINA migraine cohort were asked to complete questionnaires concerning cold extremities, sleep quality and migraine. Results: A total of 594 migraine patients and 199 controls completed the questionnaires. In women, thermal discomfort and cold extremities (TDCE) were more often reported by migraineurs versus controls (odds ratio 2.3, 95% confidence interval 1.4–3.7; P < 0.001), but not significantly so in men (odds ratio 2.5, 95% confidence interval 0.9–6.9; P = 0.09). There was no difference in TDCE comparing migraine with or without aura. Female migraineurs who reported TDCE had higher attack frequencies compared to female migraineurs without TDCE (4 vs. 3 attacks per month; P = 0.003). The association between TDCE and attack frequency was mediated by the presence of difficulty initiating sleep (P = 0.02). Conclusion: Women with migraine more often reported cold extremities compared with controls, possibly indicating a sex-specific vascular vulnerability. Female migraineurs with cold extremities had higher attack frequencies, partly resulting from sleep disturbances. Future studies need to demonstrate whether cold extremities in female migraineurs are a predictor for cardiovascular and cerebrovascular events.

Oral glucose ingestion leads to impaired muscle microvascular blood flow (MBF), which may contribute to acute hyperglycemia-induced insulin resistance. We investigated whether incorporating lipids and protein into a high-glucose load would prevent postprandial MBF dysfunction. Ten healthy young men (age, 27 yr [24, 30], mean with lower and upper bounds of the 95% confidence interval; height, 180 cm [174, 185]; weight, 77 kg [70, 84]) ingested a high-glucose (1.1 g/kg glucose) mixed-nutrient meal (10 kcal/kg; 45% carbohydrate, 20% protein, and 35% fat) in the morning after an overnight fast. Femoral arterial blood flow was measured via Doppler ultrasound, and thigh MBF was measured via contrast-enhanced ultrasound, before meal ingestion and 1 h and 2 h postprandially. Blood glucose and plasma insulin were measured at baseline and every 15 min throughout the 2-h postprandial period. Compared with baseline, thigh muscle microvascular blood volume, velocity, and flow were significantly impaired at 60 min postprandial (−25%, −27%, and −46%, respectively; all P < 0.05) and to a greater extent at 120 min postprandial (−37%, −46%, and −64%; all P < 0.01). Heart rate and femoral arterial diameter, blood velocity, and blood flow were significantly increased at 60 min and 120 min postprandial (all P < 0.05). Higher blood glucose area under the curve was correlated with greater MBF dysfunction ( R2 = 0.742; P < 0.001). Ingestion of a high-glucose mixed-nutrient meal impairs MBF in healthy individuals for up to 2 h postprandial

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) may lower cardiovascular disease risk by reducing blood pressure (BP). We hypothesized that fat-1 transgenic mice, which convert n-6 PUFAs to n-3 PUFAs, would have improved vascular function in BP regulation and following secondhand smoke (SHS) exposure, compared to wild type (WT) mice. BP was recorded in mice fed an n-6 PUFA, or standard chow diet. On the n-6 PUFA diet fat-1 mice had a lower mean arterial pressure and a greater decrease in diastolic BP when treated with an ACE inhibitor, compared to WT mice. No differences were observed on the chow diet. Next, fat-1 mice on the n-6 PUFA or chow diet were exposed to SHS. SHS enhanced vasoconstriction on the n-6 PUFA diet, but not on chow, but did not affect vasorelaxation. These data suggest n-3 PUFAs have a protective role in basal BP regulation and SHS-induced vascular dysfunction.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) may lower cardiovascular disease risk by reducing blood pressure (BP). We hypothesized that fat-1 transgenic mice, which convert n-6 PUFAs to n-3 PUFAs, would have improved vascular function in BP regulation and following secondhand smoke (SHS) exposure, compared to wild type (WT) mice. BP was recorded in mice fed an n-6 PUFA, or standard chow diet. On the n-6 PUFA diet fat-1 mice had a lower mean arterial pressure and a greater decrease in diastolic BP when treated with an ACE inhibitor, compared to WT mice. No differences were observed on the chow diet. Next, fat-1 mice on the n-6 PUFA or chow diet were exposed to SHS. SHS enhanced vasoconstriction on the n-6 PUFA diet, but not on chow, but did not affect vasorelaxation. These data suggest n-3 PUFAs have a protective role in basal BP regulation and SHS-induced vascular dysfunction.

Voltage-gated potassium (KV ) channels are key regulators of vascular smooth muscle contractility and vascular tone, and thus have major influence on the microcirculation. KV channels are important determinants of vascular smooth muscle membrane potential (Em ). A number of KV subunits are expressed in the plasma membrane of smooth muscle cells. Each subunit confers distinct kinetics and regulatory properties that allow for fine control of Em to orchestrate vascular tone. Modifications in KV subunit expression and/or channel activity can contribute to changes in vascular smooth muscle contractility in response to different stimuli and in diverse pathological conditions. Consistent with this, a number of studies suggest alterations in KV subunit expression and/or function as underlying contributing mechanisms for small resistance artery dysfunction in pathologies such as hypertension and metabolic disorders, including diabetes. Here, we review our current knowledge on the effects of these pathologies on KV channel expression and function in vascular smooth muscle cells, and the repercussions on (micro)vascular function.

Given the demand for developing objective methods for characterizing traumatic brain injury (TBI), research dedicated to evaluating putative biomarkers has burgeoned over the past decade. Since it is critical to elucidate the underlying pathological processes that underlie the higher diverse outcomes that follow neurotrauma, considerable efforts have been aimed at identifying biomarkers of both the acute- and chronic-phase TBI. Such information is not only critical for helping to elucidate the pathological changes that lead to poor long-term outcomes following TBI but it may also assist in the identification of possible prevention and interventions for individuals who sustain head trauma. In the current review, we discuss the potential role of vascular dysfunction and chronic inflammation in both acute- and chronic-phase TBI, and we also highlight existing studies that have investigated inflammation biomarkers associated with poorer injury outcome.

Accumulation of amyloid β (Aβ) and its aggregates in the ageing central nervous system is regarded synonymous to Alzheimer’s disease (AD) pathology. Despite unquestionable advances in mechanistic and diagnostic aspects of the disease understanding, the primary cause of Aβ accumulation as well as its in vivo roles remains elusive; nonetheless, the majority of the efforts to address pathological mechanisms for therapeutic development are focused towards moderating Aβ accumulation in the brain. More recently, Aβ deposition has been identified in the eye and is linked with distinct age-related diseases including age-related macular degeneration, glaucoma as well as AD. Awareness of the Aβ accumulation in these markedly different degenerative disorders has led to an increasing body of work exploring overlapping mechanisms, a prospective biomarker role for Aβ and the potential to use retina as a model for brain related neurodegenerative disorders. Here, we present an integrated view of current understanding of the retinal Aβ deposition discussing the accumulation mechanisms, anticipated impacts and outlining ameliorative approaches that can be extrapolated to the retina for potential therapeutic benefits. Further longitudinal investigations in humans and animal models will determine retinal Aβ association as a potential pathognomonic, diagnostic or prognostic biomarker. © 2016 Springer International Publishing

p66(shc), a member of the ShcA protein family, is essential for cellular response to oxidative stress, and elicits the formation of mitochondrial Reactive Oxygen Species (ROS), thus promoting vasomotor dysfunction and inflammation. Accordingly, mice lacking the p66 isoform display increased resistance to oxidative tissue damage and to cardiovascular disorders. Oxidative stress also contributes to noise-induced hearing loss (NIHL); we found that p66(shc) expression and serine phosphorylation were induced following noise exposure in the rat cochlea, together with markers of oxidative stress, inflammation and ischemia as indicated by the levels of the hypoxic inducible factor (HIF) and the vascular endothelial growth factor (VEGF) in the highly vascularised cochlear lateral region and spiral ganglion. Importantly, p66(shc) knock-out (p66 KO) 126 SvEv adult mice were less vulnerable to acoustic trauma with respect to wild type controls, as shown by preserved auditory function and by remarkably lower levels of oxidative stress and ischemia markers. Of note, decline of auditory function observed in 12 month old WT controls was markedly attenuated in p66KO mice consistent with delayed inner ear senescence. Collectively, we have identified a pivotal role for p66(shc) -induced vascular dysfunction in a common pathogenic cascade shared by noise-induced and age-related hearing loss.

OBJECTIVE: To test the hypothesis that the inverse association between infant growth and endothelial function at 6 months would persist to 24 months and that accelerated growth would lead to an increased percent body fat, which would, in turn, impact negatively on endothelial function. STUDY DESIGN: In a prospective observational study, 104 healthy term newborns underwent anthropometry and measurements of vascular vasodilation at 0, 6, 12, and 24 months. We recorded maximum vasodilation in response to acetylcholine (endothelium-dependent) and nitroprusside (endothelium-independent) by use of laser-Doppler vascular perfusion monitoring of the forearm skin vasculature. Additional anthropometry at 1 and 3 months was collected from child welfare centers. The data were analyzed by multilevel linear regression. RESULTS: Weight gain from 0-1 month was associated inversely with maximum perfusion in response to acetylcholine at the age of 2 years (b = -8.28 perfusion units [PU] per Delta z-score, P = .03). Weight gain from 0-1 month was related positively to maximum perfusion in response to nitroprusside (b = 10.12 PU per Delta z-score, P = .04), as was birth weight (b = 8.02 PU per z-score, P = .02). Body fat percentage did not have a significant effect in any of the perfusion models and was not related to maximum perfusion at 2 years. CONCLUSION: Infant weight gain from 0-1 month is inversely related to endothelial function in healthy term infants, at least to the age of 2 years. This relationship was not explained by an increased percentage body fat.

This dissertation focussed on the damaging effects of deterioration of vascular function on the body. It is shown that deterioration of function of large blood vessels (due to vascular stiffening), small blood vessels (microvascular dysfunction) and the lining of blood vessels (endothelial dysfunction) not only plays an important role in the development of cardiovascular disease, but also in the development of dementia and depression. Vascular dysfunction is therefore an important new lead for preventing and treating cardiovascular disease, dementia and depression. Various studies were used, including the Maastricht Study, the Hoorn Study, the AGES-Reykjavik Study and the Rotterdam Study.

Sarcopenia, the age-related loss of muscle mass and function, imposes a dramatic burden on individuals and society. The development of preventive and therapeutic strategies against sarcopenia is therefore perceived as an urgent need by health professionals and has instigated intensive research on the pathophysiology of this syndrome. The pathogenesis of sarcopenia is multifaceted and encompasses lifestyle habits, systemic factors (e.g., chronic inflammation and hormonal alterations), local environment perturbations (e.g., vascular dysfunction), and intramuscular specific processes. In this scenario, derangements in skeletal myocyte mitochondrial function are recognized as major factors contributing to the age-dependent muscle degeneration. In this review, we summarize prominent findings and controversial issues on the contribution of specific mitochondrial processes - including oxidative stress, quality control mechanisms and apoptotic signaling - on the development of sarcopenia. Extramuscular alterations accompanying the aging process with a potential impact on myocyte mitochondrial function are also discussed. We conclude with presenting methodological and safety considerations for the design of clinical trials targeting mitochondrial dysfunction to treat sarcopenia. Special emphasis is placed on the importance of monitoring the effects of an intervention on muscle mitochondrial function and identifying the optimal target population for the trial. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. © 2013 Elsevier Ltd. All rights reserved.

Aim. Serum γ-glutamyltransferase (GGT) is increasingly regarded as a marker of vascular function. However, the usefulness of this marker is in dispute. Gender and ethnic differences, as well as the serum level range where correlations with vascular function will emerge, may complicate the usefulness of GGT. The aim is to compare correlations with markers of vascular function between African and Caucasian groups. Methods. This cross-sectional target population study involved four groups of African and Caucasian men and women of 100 participants each. Fasting lipids, GGT, C-reactive protein (CRP), reactive oxygen species, and glycosylated hemoglobin (HbA1c) were determined as well as blood pressure, carotid intima-media thickness (CIMT), and left ventricular hypertrophy. Results. γ-Glutamyltransferase levels were significantly higher in Africans compared with Caucasians and also higher in men than in women. γ-Glutamyltransferase correlated with triglycerides in all four groups and after adjusting the correlations sustained in the male groups but disappeared in women. Correlations existed between GGT and blood pressure, except for the African women. After adjustments, CIMT correlated with GGT in Caucasian men (r = 0.29; P < .01). Glycosylated hemoglobin was associated with GGT in Caucasian women (r = 0.26; P = .01) as well as CRP (r = 0.36; P < .01). When the groups were divided into low and high GGT groups by median split, most of the correlations disappeared in the high GGT groups. Conclusions. Gender and ethnic-specific associations occurred regarding GGT and variables associated with cardiovascular function. With high levels of GGT the correlations diminished. The usefulness of GGT as a marker of vascular dysfunction seems limited.

Aim. Serum γ-glutamyltransferase (GGT) is increasingly regarded as a marker of vascular function. However, the usefulness of this marker is in dispute. Gender and ethnic differences, as well as the serum level range where correlations with vascular function will emerge, may complicate the usefulness of GGT. The aim is to compare correlations with markers of vascular function between African and Caucasian groups. Methods. This cross-sectional target population study involved four groups of African and Caucasian men and women of 100 participants each. Fasting lipids, GGT, C-reactive protein (CRP), reactive oxygen species, and glycosylated hemoglobin (HbA1c) were determined as well as blood pressure, carotid intima-media thickness (CIMT), and left ventricular hypertrophy. Results. γ-Glutamyltransferase levels were significantly higher in Africans compared with Caucasians and also higher in men than in women. γ-Glutamyltransferase correlated with triglycerides in all four groups and after adjusting the correlations sustained in the male groups but disappeared in women. Correlations existed between GGT and blood pressure, except for the African women. After adjustments, CIMT correlated with GGT in Caucasian men (r = 0.29; P < .01). Glycosylated hemoglobin was associated with GGT in Caucasian women (r = 0.26; P = .01) as well as CRP (r = 0.36; P < .01). When the groups were divided into low and high GGT groups by median split, most of the correlations disappeared in the high GGT groups. Conclusions. Gender and ethnic-specific associations occurred regarding GGT and variables associated with cardiovascular function. With high levels of GGT the correlations diminished. The usefulness of GGT as a marker of vascular dysfunction seems limited.

Background: Smoking is an important modifiable risk factor for cardiovascular disease, with limited research having been done in Africans. We aimed to determine the association between smoking and measurements of vascular function in Africans and Caucasians. Methods: We determined anthropometric and cardiovascular variables, serum cotinine and C-reactive protein (CRP) in African and Caucasian participants from South Africa (n = 630). Results: Africans had significantly lower body mass index (BMI), higher blood pressure and lower socio-economic status (SES) than Caucasians. Only African smokers showed increased arterial stiffness and a significant correlation between smoking and arterial stiffness. African smokers had increased and Caucasian smokers decreased high-density lipoprotein cholesterol (HDL-C) than the non-smokers. After adjusting for confounders, smoking showed few correlations, mainly with heart rate and CRP. In Africans, smoking also correlated positively with HDL-C, with the opposite result in Caucasians. Conclusion: African smokers had significantly increased arterial stiffness, which was not found in Caucasian smokers. Africans generally demonstrated more associations between smoking and cardiovascular dysfunction than Caucasians.

Background: Smoking is an important modifiable risk factor for cardiovascular disease, with limited research having been done in Africans. We aimed to determine the association between smoking and measurements of vascular function in Africans and Caucasians. Methods: We determined anthropometric and cardiovascular variables, serum cotinine and C-reactive protein (CRP) in African and Caucasian participants from South Africa (n = 630). Results: Africans had significantly lower body mass index (BMI), higher blood pressure and lower socio-economic status (SES) than Caucasians. Only African smokers showed increased arterial stiffness and a significant correlation between smoking and arterial stiffness. African smokers had increased and Caucasian smokers decreased high-density lipoprotein cholesterol (HDL-C) than the non-smokers. After adjusting for confounders, smoking showed few correlations, mainly with heart rate and CRP. In Africans, smoking also correlated positively with HDL-C, with the opposite result in Caucasians. Conclusion: African smokers had significantly increased arterial stiffness, which was not found in Caucasian smokers. Africans generally demonstrated more associations between smoking and cardiovascular dysfunction than Caucasians.

Caveolae and lipid rafts are plasma membrane microdomains that are considered to play a role in cellular signalling. Caveolins and cavins as well as cholesterol are required for the structure and function of caveolae. The papers summarized in this thesis examine the role of caveolae in smooth muscle function. Ca2+-sensitization is a contractile process depending on inhibition of myosin phosphatase activity. Here I test whether protein kinase C and Rho-associated kinase-mediated Ca2+ sensitization depends on caveolae using gene disrupted (KO) mice. While the process of Ca2+ sensitization was unaffected by lack of caveolae in the intestine, α1-adrenergic and protein kinase C-mediated arterial contraction was increased. Arteries lacking caveolae weighed more per unit length, suggesting growth of the arterial wall. I go on to demonstrate that small resistance arteries from KO mice are remodelled, and that these and other changes counterbalance an excessive NO production to normalize blood pressure in caveolin-1 deficient mice. NO production is required for initiating and maintaining penile erection. Surprisingly, nerve-induced relaxation and relaxation in response carbachol and sodium nitroprusside was impaired in caveolae-deficient corpus cavernosum. In the last two papers, I examine the role of caveolae in detrusor function. Disruption of caveolae using desorption of cholesterol was first shown to impair contraction of human bladder strips in response to muscarinic receptor activation. I then demonstrate that the membrane density of caveolae increases after bladder outlet obstruction in the rat. The latter effect was due to crowding of the same relative number of caveolin molecules on a smaller relative membrane area. In conclusion, a considerable body of evidence has been gathered that demonstrate an important and pleiotropic physiological and pathophysiological role of caveolae in smooth muscle

During the last 10 years, a lot of progress has been made in unraveling the pathogenic cascade leading to Alzheimer s disease (AD). However, some important aspects of the disease mechanism are not yet fully understood. In particular, there is no consensus as yet on whether the disease acts through a loss or a gain of function mechanism (Van Broeck et al, 2007). AD and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of AD (Zhu et al, 2007). AD is associated with considerably decreased cerebral blood flow (CBF) thought to be secondary, since dead neurons do not need oxygen and glucose. This view has been critically re-examined and AD has been re-evaluated by some researchers as a disorder caused by primary and not by secondary CBF deficiency. In fact, some experimental evidence indicates that dysfunction of the neurovascular unit may be an early event in AD and could provide a potential link between this disorder and cerebral ischemia (Iadecola, 2004). This new approach opens new possibilities for treatment and prevention (Niedermeyer, 2006).