Vascular dysfunction in offspring of preeclampsia is related to preeclampsia per se rather than genetically determined

Objectives: Epidemiological studies suggest that adverse events in utero may predispose to premature cardiovascular disease in adulthood, but the mechanisms are not known. Recently, we found that young apparently healthy offspring of mothers with preeclampsia (PE) display systemic endothelial dysfunction. This problem could be related to PE per se or to a genetic abnormality that predisposes the mother to PE and the offspring to vascular dysfunction. To distinguish between these two possibilities, we assessed vascular function in offspring of PE, their siblings who were born after a normal pregnancy, and in control subjects.Methods: We measured endothelium-dependent vasodilation (flow-mediated vasodilation, FMD), in 10 pairs of healthy normotensive siblings, one born after PE (age 15±6 y; mean±SD), the other after normal pregnancy (17±6y) and in 17 (16±7y) controls. All subjects were born at term.Results: The vascular function in siblings of PE who were born after normal pregnancy was normal and comparable to the one in controls (8.6±1.5% vs. 8.1±1.3%, P=0.32), whereas offspring of PE displayed a roughly 30% smaller FMD than the two other groups (5.9±1.6%, P<0.005 vs. both siblings and controls, Figure). The endothelial dysfunction in the offspring of PE was not related to a difference in the central arterial blood pressure or arterial oxygen saturation, because they were comparable in the 3 groups. Figure 1. FMD in the three groups.Conclusions: These findings provide the first evidence that vascular dysfunction in offspring of PE is caused by PE itself, rather than by a genetic abnormality that predisposes the mother to PE and the offspring to a vascular defect. Prevention of PE and/or its successful treatment is expected to prevent vascular dysfunction and premature cardiovascular morbidity and mortality in the offspring.

Endogenous cannabinoid receptor CB1 activation promotes vascular smooth-muscle cell proliferation and neointima formation.

Percutaneous transluminal angioplasty is frequently used in patients with severe arterial narrowing due to atherosclerosis. However, it induces severe arterial injury and an inflammatory response leading to restenosis. Here, we studied a potential activation of the endocannabinoid system and the effect of FA amide hydrolase (FAAH) deficiency, the major enzyme responsible for endocannabinoid anandamide degradation, in arterial injury. We performed carotid balloon injury in atherosclerosis-prone apoE knockout (apoE(-/-)) and apoE(-/-)FAAH(-/-) mice. Anandamide levels were systemically elevated in apoE(-/-) mice after balloon injury. ApoE(-/-)FAAH(-/-) mice had significantly higher baseline anandamide levels and enhanced neointima formation compared with apoE(-/-) controls. The latter effect was inhibited by treatment with CB1 antagonist AM281. Similarly, apoE(-/-) mice treated with AM281 had reduced neointimal areas, reduced lesional vascular smooth-muscle cell (SMC) content, and proliferating cell counts. The lesional macrophage content was unchanged. In vitro proliferation rates were significantly reduced in CB1(-/-) SMCs or when treating apoE(-/-) or apoE(-/-)FAAH(-/-) SMCs with AM281. Macrophage in vitro adhesion and migration were marginally affected by CB1 deficiency. Reendothelialization was not inhibited by treatment with AM281. In conclusion, endogenous CB1 activation contributes to vascular SMC proliferation and neointima formation in response to arterial injury.

Vascular Effects of RWJ-676070, a Selective Combined V-1a/V-2 Vasopressin Receptor Antagonist

In recent years, several vasopressin antagonists have been developed that block V-1 receptors either selectively or nonselectively.(1,2) To date, one combined V-1/V-2 antagonist (primarily a V-2 antagonist, as determined on the basis of human receptor binding data), conivaptan, has been approved for the treatment of euvolemic hyponatremia.(3,4) We have previously shown that the vascular properties of a vasopressin V-1 antagonist can be investigated safely and reliably in healthy subjects. We used the measurement of skin blood flow after intradermic injection of exogenous arginine vasopressin on a skin area prevasodilated with calcitonin gene-related peptide (CGRP).(3,5) This technique enables the documentation of the dose-dependent effects of vasopressin or vasopressin antagonists. In this study, we have characterized the V-1a pharmacodynamic profile of increasing doses of RWJ-676070, a new orally active dual V-1a/V-2 receptor antagonist, in healthy subjects.(5)

Constraints on the permeability structure of alluvial aquifers from the poro-elastic inversion of multi-frequency P-wave velocity logs

We have explored the possibility of obtaining first-order permeability estimates for saturated alluvial sediments based on the poro-elastic interpretation of the P-wave velocity dispersion inferred from sonic logs. Modern sonic logging tools designed for environmental and engineering applications allow one for P-wave velocity measurements at multiple emitter frequencies over a bandwidth covering 5 to 10 octaves. Methodological considerations indicate that, for saturated unconsolidated sediments in the silt to sand range and typical emitter frequencies ranging from approximately 1 to 30 kHz, the observable velocity dispersion should be sufficiently pronounced to allow one for reliable first-order estimations of the permeability structure. The corresponding predictions have been tested on and verified for a borehole penetrating a typical surficial alluvial aquifer. In addition to multifrequency sonic logs, a comprehensive suite of nuclear and electrical logs, an S-wave log, a litholog, and a limited number laboratory measurements of the permeability from retrieved core material were also available. This complementary information was found to be essential for parameterizing the poro-elastic inversion procedure and for assessing the uncertainty and internal consistency of corresponding permeability estimates. Our results indicate that the thus obtained permeability estimates are largely consistent with those expected based on the corresponding granulometric characteristics, as well as with the available evidence form laboratory measurements. These findings are also consistent with evidence from ocean acoustics, which indicate that, over a frequency range of several orders-of-magnitude, the classical theory of poro-elasticity is generally capable of explaining the observed P-wave velocity dispersion in medium- to fine-grained seabed sediments

The permeability P-glycoprotein: a focus on enantioselectivity and brain distribution.

IMPORTANCE OF THE FIELD: The permeability glycoprotein (P-gp) is an important protein transporter involved in the disposition of many drugs with different chemical structures, but few studies have examined a possible stereoselectivity in its activity. P-gp can have a major impact on the distribution of drugs in selected organs, including the brain. Polymorphisms of the ABCB1 gene, which encodes for P-gp, can influence the kinetics of several drugs. AREAS COVERED IN THIS REVIEW: A search including publications from 1990 up to 2009 was performed on P-gp stereoselectivity and on the impact of ABCB1 polymorphisms on enantiomer brain distribution. WHAT THE READER WILL GAIN: Despite stereoselectivity not being expected because of the large variability of chemical structures of P-gp substrates, structure-activity relationships suggest different P-gp-binding sites for enantiomers. Enantioselectivity in the activity of P-gp has been demonstrated by in vitro studies and in animal models (preferential transport of one enantiomer or different inhibitory potencies towards P-gp activity between enantiomers). There is also in vivo evidence of an enantioselective drug transport at the human blood-brain barrier. TAKE HOME MESSAGE: The significant enantioselective activity of P-gp might be clinically relevant and must be taken into account in future studies.

La programmmation foetale de la dysfonction vasculaire pulmonaire chez la souris : rôle des mécanismes épigénétiques = Fetal programming of pulmonary vascular dysfunction in mice : role of epigenetic mechanisms

Rapport de synthèseDes événements pathologiques survenant pendant la période foetale prédisposent la descendance aux maladies cardiovasculaires systémiques. Il existe peu de connaissances au sujet de la circulation pulmonaire et encore moins quant aux mécanismes sous-jacents. La sous-alimentation maternelle pendant la grossesse peut représenter un modèle d'investigation de ces mécanismes, parce que chez l'animal et l'homme elle est associée à une dysfonction vasculaire systémique chez la progéniture. Chez le rat, la diète restrictive pendant la grossesse induit une augmentation du stress oxydatif dans le placenta. Les dérivés de l'oxygène sont connus pour induire des altérations épigénétiques et peuvent traverser la barrière placentaire. Nous avons dès lors spéculé que chez la souris la diète restrictive pendant la grossesse induit une dysfonction vasculaire pulmonaire chez sa progéniture qui serait liée à un mécanisme épigénétique.Pour tester cette hypothèse, nous avons examiné la fonction vasculaire pulmonaire et la méthylation de l'ADN pulmonaire à la fin de 2 semaines d'exposition à l'hypoxie chez la progéniture de souris soumises à une diète restrictive pendant la grossesse et des souris contrôles. Nous avons trouvé que la vasodilatation endothélium-dépendante de l'artère pulmonaire in vitro était défectueuse, et que l'hypertension pulmonaire et l'hypertrophie ventriculaire droite induites par l'hypoxie in vivo étaient exagérées chez la progéniture de souris soumises à une diète restrictive pendant la grossesse. Cette dysfonction vasculaire pulmonaire était associée avec une altération de la méthylation de l'ADN pulmonaire. L'administration d'inhibiteurs de la déacétylase des histones, le Butyrate et la Trichostatine-A à la progéniture de souris soumises à une diète restrictive pendant la grossesse a normalisé la méthylation de l'ADN et la fonction vasculaire pulmonaire. Finalement, l'administration du nitroxyde Tempol aux mères durant la diète restrictive pendant la grossesse a prévenu la dysfonction vasculaire et la dysméthylation chez la progéniture.Ces découvertes démontrent que chez la souris la sous-alimentation pendant la gestation induit une dysfonction vasculaire chez la progéniture qui est causée par un mécanisme épigénétique. Il est possible qu'un mécanisme similaire soit impliqué dans la programmation foetale de la dysfonction vasculaire chez les humains.

Vascular integrins in tumor angiogenesis: mediators and therapeutic targets.

The notion that tumor angiogenesis may have therapeutic implications in the control of tumor growth was introduced by Dr. Judah Folkman in 1971. The approval of Avastin in 2004 as the first antiangiogenic systemic drug to treat cancer patients came as a validation of this visionary concept and opened new perspectives to the treatment of cancer. In addition, this success boosted the field to the quest for new therapeutic targets and antiangiogenic drugs. Preclinical and clinical evidence indicate that vascular integrins may be valid therapeutic targets. In preclinical studies, pharmacological inhibition of integrin function efficiently suppressed angiogenesis and inhibited tumor progression. alphaVbeta3 and alphaVbeta5 were the first vascular integrins targeted to suppress tumor angiogenesis. Subsequent experiments revealed that at least four additional integrins (i.e., alpha1beta1, alpha2beta1, alpha5beta1, and alpha6beta4) might be potential therapeutic targets. In clinical studies low-molecular-weight integrin inhibitors and anti-integrin function-blocking antibodies demonstrated low toxicity and good tolerability and are now being tested in combination with radiotherapy and chemotherapy for anticancer activity in patients. In this article the authors review the role of integrins in angiogenesis, present recent development in the use of alphaVbeta3 and alpha5beta1 integrin antagonists as potential therapeutics in cancer, and discuss future perspectives.

Addicions a la flora vascular del Parc Natural del Cadí-Moixeró i de les serres veïnes (Prepirineus Orientals Ibèrics)

Additions to the vascular flora of the Cadí-Moixeró Natural Park and neighbouring Pre-Pyrenean areas (eastern Iberian Pyrenees) We present about fifty contributions to the catalogue of the vascular flora of the mentioned area, published in 2003. Among the taxa reported, 21 correspond to novelties found in our own field observations or in the literature. We highlight the first records for the Eastern Iberian Pre-Pyrenees of Meconopsis cambrica (L.) Vig. and Omalotheca hoppeana (Koch) Schulz Bip. and F.W. Schulz. Other data refer to rare taxa already included in the catalogue, such as Gagea lutea (L.) Ker Gawl., G. reverchonii Degen, Lappula deflexa (Wahlenb.) Garcke and Minuartia villarii (Balb.) Wilczek and Chenevard.

Site-specific coupling between vascular wall thickness and function: an observational MRI study of vessel wall thickening and stiffening in hypertension.

OBJECTIVES: The objective of this study was to evaluate associations between aortic pulse wave velocity (PWV) and aortic and carotid vessel wall thickness (VWT) using cardiovascular magnetic resonance imaging (MRI) in patients with hypertension as compared with healthy adult volunteers. MATERIALS AND METHODS: Local medical ethics approval was obtained and the participants gave informed consent. Fifteen patients with hypertension (5 men and 10 women; mean [SD] age, 49 [14] years) and 15 age- and sex-matched healthy volunteers were prospectively included and compared. All participants underwent MRI examination for measuring aortic and carotid VWT and aortic PWV with well-validated MRI techniques at 1.5- and 3-T MRI systems: PWV was assessed from velocity-encoded MRI and VWT was assessed by using dual-inversion black-blood gradient-echo imaging techniques. Paired t tests were used for testing differences between the volunteers and the patients and Pearson correlation (r) and univariable and multivariable stepwise linear regression analyses were used to test associations between aortic and carotid arterial wall thickness and stiffness. RESULTS: Mean values for aortic PWV and aortic and carotid VWT (indexed for body surface area [BSA]) were all significantly higher in patients with hypertension as compared with the healthy volunteers (ie, aortic PWV, 7.0 ± 1.4 m/s vs 5.7 ± 1.3 m/s; aortic VWT/BSA, 0.12 ± 0.03 mL/m vs 0.10 ± 0.03 mL/m; carotid VWT/BSA, 0.04 ± 0.01 mL/m vs 0.03 ± 0.01 mL/m; all P < 0.01). Aortic PWV was highly correlated with aortic VWT/BSA (r = 0.76 and P = 0.002 in the patients vs r = 0.63 and P = 0.02 in the volunteers), and in the patients, aortic PWV was moderately correlated with carotid VWT/BSA (r = 0.50; P = 0.04). In the volunteers, correlation between aortic PWV and carotid VWT/BSA was not significant (r = 0.40; P = 0.13). In addition, aortic VWT/BSA was significantly correlated with carotid VWT/BSA, in both the patients (r = 0.60; P = 0.005) and volunteers (r = 0.57; P = 0.007). CONCLUSIONS: In the patients with hypertension and the healthy volunteers, the aortic PWV is associated more strongly with aortic wall thickness than with carotid wall thickness, reflecting site-specific coupling between vascular wall thickness and function.

Thrombin-sensitive dual fluorescence imaging and therapeutic agent for detection and treatment of synovial inflammation in murine rheumatoid arthritis.

We have developed a thrombin-sensitive polymeric photosensitizer prodrug (T-PS) to selectively image and eradicate inflammatory lesions in rheumatoid arthritis (RA). Thrombin is a serine protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients. T-PS consists of a polymeric backbone, to which multiple photosensitizer (PS) units are tethered via short thrombin-cleavable peptide linkers. Fluorescence emission and phototoxicity of the prodrug are efficiently quenched due to the interaction of neighboring photosensitizer units. The prodrug is passively delivered to the inflammation site via the enhanced permeability and retention (EPR) effect. Subsequent site-selective proteolytic cleavage of the peptide linkers restores its photoactivity by increasing the mutual distance between PS. Whole animal imaging in murine collagen-induced arthritis, an experimental model of RA revealed a dose-dependent fluorescence increase in arthritic paws after systemic prodrug injection. In addition, administration of T-PS resulted in much higher fluorescence selectivity for arthritic joints as compared to the free PS. Irradiation of the arthritic joints induced light dose dependent phototoxic effects such as apoptosis, vascular damage and local hemorrhage. Long-term observations showed complete regression of the latter. Irradiated non-arthritic tissues or non-irradiated arthritic tissues showed no histological effects after photodynamic therapy with T-PS. This illustrates that T-PS can localize inflammatory lesions with excellent selectivity and induce apoptosis and vascular shut down after irradiation.

Evaluation of Asphalt Mix Permeability, MLR-90-2, 1992

Efforts to eliminate rutting on the Interstate system have resulted in 3/4 in. aggregate mixes, with 75 blow Marshall, 85% crushed aggregate mix designs. On a few of these projects paved in 1988-1989, water has appeared on the surfaces. Some conclusions have been reached by visual on-sight investigations that the water is coming from surface water, rain and melting snow gaining entry into the surface asphalt mixture, then coming back out in selected areas. Cores were taken from several Interstate projects and tested for permeability to investigate the surface water theory that supposedly happens with only the 3/4 in. mixtures. All cores were of asphalt overlays over portland cement concrete, except for the Clarke County project which is full depth AC. The testing consisted of densities, permeabilities, voids by high pressure airmeter (HPAM), extraction, gradations, AC content, and film thicknesses. Resilient modulus, indirect tensile and retained strengths after freeze/thaw were also done. All of the test results are about as expected. Permeabilities, the main reason for testing, ranged from 0.00 to 2.67 ft per day and averages less than 1/2 ft per day if the following two tests are disregarded. One test on each binder course came out to 15.24 ft/day, and a surface course at 13.78 ft/day but these are not out of supposedly problem projects.

Permeability of Granular Subbase Materials, MLR-90-4, 1991

The purpose of this research was to evaluate the materials Iowa uses as a granular subbase and to determine if it provides adequate drainage. Numerous laboratory and in-situ tests were conducted on the materials currently being used in Iowa. The follow conclusions can be made based on the test results: 1. The crushed concrete that is used as a subbase material has a relatively low permeability compared to many other materials used by other states. 2. Further research and tests are needed to find the necessary parameters for crushed concrete to make sure it is providing its optimum drainage and preventing premature damage of the pavement. 3. We have definitely made improvements in drainage in the past few months, but there are many areas that we can improve on that will increase the permeability of this material and insure that the pavement system is safe from premature damage due to water. The current gradation specification for granular subbase material at the start of this study was: Sieve # % Passing 1” 100 #8 10-35 #50 0-15 #200 0-6

Interhemispheric distribution of Alzheimer disease and vascular pathology in brain aging

BACKGROUND AND PURPOSE: Most of the neuropathological studies in brain aging were based on the assumption of a symmetrical right-left hemisphere distribution of both Alzheimer disease and vascular pathology. To explore the impact of asymmetrical lesion formation on cognition, we performed a clinicopathological analysis of 153 cases with mixed pathology except macroinfarcts. METHODS: Cognitive status was assessed prospectively using the Clinical Dementia Rating scale; neuropathological evaluation included assessment of Braak neurofibrillary tangle and Ass deposition staging, microvascular pathology, and lacunes. The right-left hemisphere differences in neuropathological scores were evaluated using the Wilcoxon signed rank test. The relationship between the interhemispheric distribution of lesions and Clinical Dementia Rating scores was assessed using ordered logistic regression. RESULTS: Unlike Braak neurofibrillary tangle and Ass deposition staging, vascular scores were significantly higher in the left hemisphere for all Clinical Dementia Rating scores. A negative relationship was found between Braak neurofibrillary tangle, but not Ass staging, and vascular scores in cases with moderate to severe dementia. In both hemispheres, Braak neurofibrillary tangle staging was the main determinant of cognitive decline followed by vascular scores and Ass deposition staging. The concomitant predominance of Alzheimer disease and vascular pathology in the right hemisphere was associated with significantly higher Clinical Dementia Rating scores. CONCLUSIONS: Our data show that the cognitive impact of Alzheimer disease and vascular lesions in mixed cases may be assessed unilaterally without major information loss. However, interhemispheric differences and, in particular, increased vascular and Alzheimer disease burden in the right hemisphere may increase the risk for dementia in this group.