Role of Microvascular Tone and Extracellular Matrix Contraction in the Regulation of Interstitial Fluid: Implications for Aortic Dissection.

The pathophysiology of aortic dissection is poorly understood, and its risk is resistant to medical treatment. Most studies have focused on a proposed pathogenic role of transforming growth factor-β in Marfan disease and related thoracic aortic aneurysms and aortic dissections. However, clinical testing of this concept using angiotensin II type 1 receptor antagonists to block transforming growth factor-β signaling fell short of promise. Genetic mutations that predispose to thoracic aortic aneurysms and aortic dissections affect components of the extracellular matrix and proteins involved in cellular force generation. Thus, a role for dysfunctional mechanosensing in abnormal aortic wall remodeling is emerging. However, how abnormal mechanosensing leads to aortic dissection remains a mystery. Here, we review current knowledge about the regulation of interstitial fluid dynamics and myogenic tone and propose that alteration in contractile force reduces vascular tone in the microcirculation (here, aortic vasa vasorum) and leads to elevations of blood flow, transmural pressure, and fluid flux into the surrounding aortic media. Furthermore, reduced contractile force in medial smooth muscle cells coupled with alteration of structural components of the extracellular matrix limits extracellular matrix contraction, further promoting the formation of intramural edema, a critical step in the initiation of aortic dissection. The concept is supported by several pathophysiological and clinical observations. A direct implication of this concept is that drugs that lower blood pressure and limit interstitial fluid accumulation while preserving or increasing microvascular tone would limit the risk of dissection. In contrast, drugs that substantially lower microvascular tone would be ineffective or may accelerate the disease and precipitate aortic dissection

Editorial Commentary Why Do We Need a Selective Angiotensin II Type 2 Receptor Agonist?

See related article, pp 722-729 T he renin-angiotensin system has a central role in the regulation of blood pressure and water balance. It is also a main target in the treatment of hypertension. Angiotensin II has 2 major receptors, the type 1 (AT 1 R) and the type 2 receptor (AT 2 R), both coupled to G proteins. Adverse vascular remodeling observed in cardiovascular diseases is attributed to AT 1 R, and a large number of relatively selective AT 1 R inhibitors are now used in patients. The effects of AT 2 R are usually presented as counteracting the effects exerted by AT 1 R. Consequently, some beneficial effects of the AT 1 R blockers (angiotensin receptor blocker) are commonly attributed to AT 2 R activation. 1 Beneficial vascular effects of AT 2 R have now been proven by several studies. For example, AT 2 R stimulation reduces vascular RhoA/Rho kinase/myosin light chain phosphorylation in angiotensin II and AT 1 R antagonist valsartan-treated vascular smooth muscle cells in vitro, as well as in the aorta of spontaneously hypertensive rats chronically treated with candesartan. 2 Altogether, previous studies suggest a role for vascular AT 2 R in blood pressure lowering during chronic AT 1 R blockade. Similarly, in hypertensive diabetic patients, chronic angiotensin receptor blocker treatment increases AT 2 R expression level and AT 2 R-dependent vasodilatation of mesenteric resistance arteries. 3 Nevertheless, in the absence of AT 1 R inhibition, expression of AT 2 R varies a lot under physiological and pathophysiological conditions, 4 and the relatively low selectivity of the antagonist PD123319 and the weak specificity of the agonist CGP42112 do not help fully understand the role of AT 2 R. Thus, its role in most cardiovascular and metabolic disorders remains poorly understood and mainly hypothetical. Consequently, the availability of the first nonpeptide AT 2 R agonist, compound 21 (C21), was seen as a major breakthrough, as described in a recent review article. 1 Indeed, C21 has protective effects after myocardial infarction and in hypertension-induced end organ damage. In different animal models, AT 2 Rs also display an anti-inflammatory effect. 1 Nevertheless, there is accumulating evidence that the commonly accepted scheme with a balance between a constrictor effect of AT 1 R and a dilator effect of AT 2 R is too simplistic and does not always reflect experimental evidence. The work performed by Verdonk et al, 5 published in this issue of Hypertension, on the AT 2 R agonist C21 further highlights the complexity of this system, in addition to bringing key information on the mechanism of action of this new drug. Although C21 binds to AT 2 R with high affinity, this study also shows that C21 induces a puzzling combination of vasodilation and vasoconstriction. Surprisingly, C21-mediated vasodilation was independent of AT 2 R and of the endothelium. Indeed, the authors have shown that C21 has a direct inhibitory effect on calcium influx into smooth muscle cells, thus leading to relaxation. C21 was tested in rat and mouse arteries, as well as human coronary arteries, and C21-dependent vasodilation through calcium entry inhibition was also observed in mice lacking the gene encoding for AT 2 R. Furthermore, in the isolated perfused heart, C21 induces an initial AT 1 R-dependent contraction followed by AT 2 R-independent dilatation. The constrictor effect of AT 2 R was more pronounced in hypertensive rats, as shown previously. 6 This article brings up 2 major issues requiring further discussion. First, C21-dependent dilatation relies mainly on calcium entry blockade without interfering with the RhoARho-kinase pathway, which has been shown to be inhibited after AT 2 R stimulation. This finding requires reanalysis of the studies showing protective effects of C21. Indeed, the organ-protective effect of C21 is compatible with the effects of the dihydropyridine calcium channel blockers, that is, reduction of proliferation, inflammation, fibrosis, and vasoconstriction. The authors also show that low doses C21 are needed to selectively block AT 2 R. Lower doses of C21 might be used after AT 1 R blockade, which induces a large increase in AT 2 R expression level. In this condition, lower doses of C21 might be sufficient to more selectively block AT 2 R. Lower-dose C21 could, thus, be useful in resistant hypertension, although in this case its effect on calcium currents might also be advantageous. Low-dose C21 might also provide additional protection against organ damage in kidney and heart diseases in patients treated with angiotensin receptor blockers. Nevertheless, no data are yet available to support this assumption. It should be noted that more and more patients, not only hypertensive patients, receive angiotensin receptor blockers. In these conditions, a better knowledge of the effect of AT 2 R stimulation is essential, especially in the different organs affected by cardiovascular diseases. Second, this work further confirms with straightforward experiment

0166: Changes in resistance arteries expression of extracellular nucleotides signaling partners during arterial hypertension

Cardiovascular diseases are the leading cause of mortality in industrialized countries and their prevalence increases with aging populations. Small arteries constitute the main site of peripheral vascular resistance and play a key role in the regulation of blood pressure. Vascular tone is exacerbated in hypertension (HBP) and accompanied by a hypertrophy of the arterial wall. Although signaling by extracellular nucleotides is important in vascular homeostasis its contribution to vascular pathologies affecting small arteries remains poorly understood. We evaluated here the expression pattern of nucleotides signaling pathway in resistance arteries vs aorta in mice. Genes of interest including P2 receptors, ectonucleotidases (CD39, CD73) and hemi channels (connexins, pannexins) were investigated by quantitative RT-PCR. Their expression in resistance arteries was assessed in Angiotensin II-treated mice, spontaneously hypertensive rats (SHR) and, since HBP is related to age, in 24-month old mice. Our results showed that several genes are more expressed in aorta (P2ry2 and connexin 43) while others are expressed specifically (P2rx1, connexin 37) or preferentially (P2ry6) in small arteries. The latest might be involved in pathologies affecting the small arteries. With HBP, we observed a decreased connexin 37 and 40 expression level in Angiotensin II-treated mice and in SHR respectively and both decreased with aging. Interestingly, CD39 (tone regulator) decreased in the two models of HBP and with aging. Such decrease in nucleotidase activity may enhance P2 receptors activation and increase vascular contractility/tone. This is especially true considering P2Y6 (tone promoter) that increased with aging. Further studies may allow us to evaluate the contribution of these mediators in the development of small arteries defect in aging associated or not with HBP. Signaling by extracellular nucleotides may constitute new therapeutic targets in the treatment of HBP

Absence of dystrophin in mice reduces NO-dependent vascular function and vascular density: total recovery after a treatment with the aminoglycoside gentamicin.

International audienceOBJECTIVE: Mutations in the dystrophin gene causing Duchenne's muscular dystrophy (DMD) lead to premature stop codons. In mice lacking dystrophin (mdx mice), a model for DMD, these mutations can be suppressed by aminoglycosides such as gentamicin. Dystrophin plays a role in flow (shear stress)-mediated endothelium-dependent dilation (FMD) in arteries. We investigated the effect of gentamicin on vascular contractile and dilatory functions, vascular structure, and density in mdx mice. METHODS AND RESULTS: Isolated mice carotid and mesenteric resistance arteries were mounted in arteriographs allowing continuous diameter measurements. Mdx mice showed lower nitric oxide (NO)-dependent FMD and endothelial NO synthase (eNOS) expression as well as decreased vascular density in gracilis and cardiac muscles compared with control mice. Treatment with gentamycin restored these parameters. In contrast, smooth muscle-dependent contractions as well as endothelium-dependent or -independent dilation were not affected by dystrophin deficiency or by gentamicin treatment. CONCLUSIONS: Dystrophin deficiency induces a selective defect in flow-dependent mechanotransduction, thus attenuating FMD and eNOS expression, and may contribute to low arteriolar density. These findings open important perspectives regarding the mechanism involved in the pathophysiology of genetic diseases related to premature stop codons such as DMD

0343 : Essential role of P2Y6 UDP receptor in Angiotensin-II dependent arterial hypertension

Extracellular nucleotides are responsible for pleiotropic effects in the vasculature. Uracyl nucleotides are vasoactive and trophic agents and promote inflammation. The participation of specific P2 receptors in these effects remains undefined and their potential contribution in arterial hypertension is unknown.ObjectiveTo evaluate the contribution of the UDP receptor P2Y6 in hypertension in mouse.MethodsArterial contraction was evaluated using a wire myograph. Blood pressure was measured following nucleotides iv infusion and experimental hypertension was induced either by Angiotensine-II (Ang-II 1mg/kg/j) or DOCA-salt (1%) in uni-nephrectomized mice. Histological approaches, immunofluorescence and RTqPCR were used to evaluate the nature of vascular remodeling.ResultsP2Y6 displayed the highest arterial expression level among other P2Y receptors. Contraction of conductance (thoracic aorta) and resistance (mesenteric) arteries was abrogated in P2ry6-/- mice in response to UDP and UTP while other vasoconstrictor induced normal responses. P2Y6 receptor triggered a moderated intracellular calcium increase while RhoA (calcium facilitating pathway) activation was abrogated in P2ry6-/- mice. Both genetic deletion and pharmacological blockade of P2Y6 receptor abolished Ang-II-induced blood pressure increase (40 mmHg in wild type mice). By contrast, hypertensive response in DOCA-salt was equivalent in both genotypes. Following Ang-II treatment, P2ry6-/- mice developed a reduced arterial hypertrophic remodeling and fibrosis but equivalent immune cell recruitment/infiltration compared to wild type. These changes were corroborated to reduced mRNA expressions of TGFβ and NADPH oxidase subunits.ConclusionsVascular P2Y6 receptor contributes to exaggerated vascular tone, hypertrophy and fibrosis in the context of Ang-II-dependent hypertension. Its absence or pharmacological blockade limits vascular damages and prevents blood pressure increase associated to hypertension

Quartic Curves and Their Bitangents

A smooth quartic curve in the complex projective plane has 36 inequivalent representations as a symmetric determinant of linear forms and 63 representations as a sum of three squares. These correspond to Cayley octads and Steiner complexes respectively. We present exact algorithms for computing these objects from the 28 bitangents. This expresses Vinnikov quartics as spectrahedra and positive quartics as Gram matrices. We explore the geometry of Gram spectrahedra and we find equations for the variety of Cayley octads. Interwoven is an exposition of much of the 19th century theory of plane quartics.Comment: 26 pages, 3 figures, added references, fixed theorems 4.3 and 7.8, other minor change

Characterization of radiative heat transfer in a spark-ignition engine through high-speed experiments and simulations

International audienceA combined experimental and Large-Eddy Simulation (LES) study of molecular radiation is presented for combustion in a homogeneous pre-mixed spark-ignition engine. Molecular radiation can account for ~10% of the engine heat loss and could have a noticeable impact on the local conditions within the combustion chamber. The Transparent Combustion Chamber (TCC) engine, a single-cylinder two-valve research engine with a transparent liner and piston for optical access, was used for this study. High-speed infrared emission spectroscopy and radiative post-processing of LES calculations have been performed to gain insight into the timescales and magnitude of radiative emissions of molecular gases during the combustion process. Both the measurements and simulations show significant Cycle-to-Cycle Variations (CCV) of radiative emission. There is agreement in the instantaneous radiative spectrum of experiment and simulation, but the crank-angle development of the radiative spectrum shows disagreement. The strengths and limitations of the optical experiments and radiative simulations are seen in the results and suggest pathways for future efforts in characterizing the influence of molecular radiation. In particular, focusing on the relative changes of the spectral features will be important as they contain information about the thermochemical properties of the gas mixture

Cyclooxygenase-2 Inhibition Restored Endothelium-Mediated Relaxation in Old Obese Zucker Rat Mesenteric Arteries

Metabolic syndrome is associated with reduced endothelial vasodilator function. It is also associated with the induction of cyclooxygenase-2 (COX2), which produces vasoactive prostanoids. The frequency of metabolic syndrome increases with age and aging per se is a risk factor associated with reduced endothelium-mediated relaxation. Nevertheless, the combined effect of aging and metabolic syndrome on the endothelium is less known. We hypothesized that COX2 derived prostanoids may affect endothelium function in metabolic syndrome associated with aging. We used obese Zucker rats, a model of metabolic syndrome. First order mesenteric arteries were isolated from 4- and 12-month-old rats and acetylcholine (endothelium)-dependent relaxation determined using wire-myography. Endothelium-mediated relaxation, impaired in young Zucker rats (89 versus 77% maximal relaxation; lean versus Zucker), was further reduced in old Zucker rats (72 versus 51%, lean versus Zucker). The effect of the nitric oxide-synthesis inhibitor L-NAME on the relaxation was reduced in both young and old Zucker rats without change in eNOS expression level. COX inhibition (indomethacin) improved acetylcholine-mediated relaxation in old obese rats only, suggesting involvement of vasoconstrictor prostanoids. In addition, COX2 inhibition (NS398) and TxA2/PGH2 receptor blockade (SQ29548) both improved relaxation in old Zucker rat arteries. Old Zucker rats had the highest TxB2 (TxA2 metabolite) blood level associated with increased COX2 immunostaining. Chronic COX2 blockade (Celecoxib, 3 weeks) restored endothelium-dependent relaxation in old Zucker rats to the level observed in old lean rats. Thus the combination of aging and metabolic syndrome further impairs endothelium-dependent relaxation by inducing an excessive production of COX2-derived vasoconstrictor(s); possibly TxA2

A Bayesian approach to star-galaxy classification

Star-galaxy classification is one of the most fundamental data-processing tasks in survey astronomy, and a critical starting point for the scientific exploitation of survey data. For bright sources this classification can be done with almost complete reliability, but for the numerous sources close to a survey's detection limit each image encodes only limited morphological information. In this regime, from which many of the new scientific discoveries are likely to come, it is vital to utilise all the available information about a source, both from multiple measurements and also prior knowledge about the star and galaxy populations. It is also more useful and realistic to provide classification probabilities than decisive classifications. All these desiderata can be met by adopting a Bayesian approach to star-galaxy classification, and we develop a very general formalism for doing so. An immediate implication of applying Bayes's theorem to this problem is that it is formally impossible to combine morphological measurements in different bands without using colour information as well; however we develop several approximations that disregard colour information as much as possible. The resultant scheme is applied to data from the UKIRT Infrared Deep Sky Survey (UKIDSS), and tested by comparing the results to deep Sloan Digital Sky Survey (SDSS) Stripe 82 measurements of the same sources. The Bayesian classification probabilities obtained from the UKIDSS data agree well with the deep SDSS classifications both overall (a mismatch rate of 0.022, compared to 0.044 for the UKIDSS pipeline classifier) and close to the UKIDSS detection limit (a mismatch rate of 0.068 compared to 0.075 for the UKIDSS pipeline classifier). The Bayesian formalism developed here can be applied to improve the reliability of any star-galaxy classification schemes based on the measured values of morphology statistics alone.Comment: Accepted 22 November 2010, 19 pages, 17 figure

In Utero Exposure to Maternal Diabetes Impairs Vascular Expression of Prostacyclin Receptor in Rat Offspring

International audienc