Ed van Bavel

Endothelial function in myometrial resistance arteries of normal pregnant women perfused with syncytiotrophoblast microvillous membranes

Objective To investigate the effects of syncytiotrophoblast microvillous membranes (STBM) in concentrations, found in vivo in women with pre‐eclampsia, on endothelial function in isolated resistance arteries.

k - t BLAST and SENSE accelerated time-resolved three-dimensional phase contrast MRI in an intracranial aneurysm

ObjectiveThe objective of this study was to investigate the performance of k-t BLAST (Broad-use Linear Acquisition Speed-up Technique) accelerated time-resolved 3D PC-MRI compared to SENSE (SENSitivity Encoding) acceleration in an in vitro and in vivo intracranial aneurysm.Materials and methodsNon-accelerated, SENSE and k-t BLAST accelerated time-resolved 3D PC-MRI measurements were performed in vivo and in vitro. We analysed the consequences of various temporal resolutions in vitro.ResultsBoth in vitro and in vivo measurements showed that the main effect of k-t BLAST was underestimation of velocity during systole. In the phantom, temporal blurring decreased with increasing temporal resolution. Quantification of the differences between the non-accelerated and accelerated measurements confirmed that in systole SENSE performed better than k-t BLAST in terms of mean velocity magnitude. In both in vitro and in vivo measurements, k-t BLAST had higher SNR compared to SENSE. Qualitative comparison between measurements showed good similarity.ConclusionComparison with SENSE revealed temporal blurring effects in k-t BLAST accelerated measurements.

Hypertension reduces soluble guanylyl cyclase expression in the mouse aorta via the Notch signaling pathway

Hypertension is a dominating risk factor for cardiovascular disease. To characterize the genomic response to hypertension, we administered vehicle or angiotensin II to mice and performed gene expression analyses. AngII treatment resulted in a robust increase in blood pressure and altered expression of 235 genes in the aorta, including Gucy1a3 and Gucy1b3 which encode subunits of soluble guanylyl cyclase (sGC). Western blotting and immunohistochemistry confirmed repression of sGC associated with curtailed relaxation via sGC activation. Analysis of transcription factor binding motifs in promoters of differentially expressed genes identified enrichment of motifs for RBPJ, a component of the Notch signaling pathway, and the Notch coactivators FRYL and MAML2 were reduced. Gain and loss of function experiments demonstrated that JAG/NOTCH signaling controls sGC expression together with MAML2 and FRYL. Reduced expression of sGC, correlating with differential expression of MAML2, in stroke prone and spontaneously hypertensive rats was also seen, and RNA-Seq data demonstrated correlations between JAG1, NOTCH3, MAML2 and FRYL and the sGC subunits GUCY1A3 and GUCY1B3 in human coronary artery. Notch signaling thus provides a constitutive drive on expression of the major nitric oxide receptor (GUCY1A3/GUCY1B3) in arteries from mice, rats, and humans, and this control mechanism is disturbed in hypertension.

The Effect of Creatine Kinase Inhibition on Contractile Properties of Human Resistance Arteries.

BACKGROUND Creatine kinase (CK) is a main predictor of blood pressure, and this is thought to largely depend on high resistance artery contractility. We previously reported an association between vascular contractility and CK in normotensive pregnancy, but pregnancy is a strong CK inducer, and data on human hypertension are lacking. Therefore, we further explored CK-dependency of vascular contractility outside the context of pregnancy in normotensive and hypertensive women. METHODS AND RESULTS Nineteen consecutive women, mean age 42 years (SE 1.3), mean systolic/diastolic blood pressure respectively 142.6 (SE 5.9)/85.6 (3.4) mm Hg (9 hypertensive), donated an omental fat sample during abdominal surgery. We compared vasodilation after the specific CK inhibitor 2,4-dinitro-1-fluorobenzene (DNFB; 10(-6) mol/l) to sodium nitroprusside (10(-6) mol/l) in isolated resistance arteries using a wire myograph. Additionally, we assessed predictors of vasoconstrictive force. DNFB reduced vascular contractility to 24.3% (SE 4.4), P < 0.001, compared to baseline. Sodium nitroprusside reduced contractility to 89.8% (SE 2.3). Maximum contractile force correlated with DNFB effect as a measure of CK (r = 0.8), and with vessel diameter (r = 0.7). The increase in contractile force was 16.5 mN [9.1-23.9] per unit DNFB effect in univariable and 10.35 mN [2.10-18.60] in multivariable regression analysis. CONCLUSION This study extends on our previous findings in pregnant normotensive women of CK-dependent microvascular contractility, indicating that CK contributes significantly to resistance artery contractility across human normotension and primary hypertension outside the context of pregnancy. Further studies should explore the effect of CK inhibitors on clinical blood pressure.

Endothelial basement membrane laminin 511 is essential for shear stress response

Shear detection and mechanotransduction by arterial endothelium requires junctional complexes containing PECAM‐1 and VE‐cadherin, as well as firm anchorage to the underlying basement membrane. While considerable information is available for junctional complexes in these processes, gained largely from in vitro studies, little is known about the contribution of the endothelial basement membrane. Using resistance artery explants, we show that the integral endothelial basement membrane component, laminin 511 (laminin α5), is central to shear detection and mechanotransduction and its elimination at this site results in ablation of dilation in response to increased shear stress. Loss of endothelial laminin 511 correlates with reduced cortical stiffness of arterial endothelium in vivo, smaller integrin β1‐positive/vinculin‐positive focal adhesions, and reduced junctional association of actin–myosin II. In vitro assays reveal that β1 integrin‐mediated interaction with laminin 511 results in high strengths of adhesion, which promotes p120 catenin association with VE‐cadherin, stabilizing it at cell junctions and increasing cell–cell adhesion strength. This highlights the importance of endothelial laminin 511 in shear response in the physiologically relevant context of resistance arteries.

Testosterone and β-oestradiol prevent inward remodelling of rat small mesenteric arteries: role of NO and transglutaminase

Increasing evidence shows that sex hormones exert a protective effect on the vasculature, especially in the regulation of the active vasomotor responses. However, whether sex hormones affect vascular remodelling is currently unclear. In the present study, we tested the hypothesis that testosterone in males and β-oestradiol in females prevent inward remodelling, possibly through inhibition of cross-linking activity induced by enzymes of the TG (transglutaminase) family. Small mesenteric arteries were isolated from male and female Wistar rats. Dose-dependent relaxation to testosterone and β-oestradiol was inhibited by the NO synthase inhibitor L-NAME (NG-nitro-L-arginine methyl ester), confirming that these hormones induce NO release. When arteries were cannulated, pressurized and kept in organ culture with ET-1 (endothelin-1) for 3 days we observed strong vasoconstriction and inward remodelling. Remodelling was significantly inhibited by testosterone in males, and by β-oestradiol in females. This preventive effect of sex hormones was not observed in the presence of L-NAME. Inward remodelling was also reduced by the inhibitor of TG L682.777, both in males and females. In arteries from female rats, ET-1 increased TG activity, and this effect was prevented by β-oestradiol. L-NAME induced a significant increase in TG activity in the presence of sex hormones in arteries from both genders. We conclude that testosterone and β-oestradiol prevent constriction-induced inward remodelling. Inward remodelling, both in males and females, depends on NO and TG activity. In females, inhibition of inward remodelling could be mediated by NO-mediated inhibition of TG activity.

Multiscale 3-D + t Intracranial Aneurysmal Flow Vortex Detection

Objective: Characteristics of vortices within intracranial aneurysmal flow patterns have been associated with increased risk of rupture. The classifications of these vortex characteristics are commonly based upon qualitative scores, and are, therefore, subjective to user interpretation. We present a quantitative method for automatic time-resolved characterization of 3-D flow patterns and vortex detection within aneurysms. Methods: Our approach is based upon the combination of kernel deconvolution and Jacobian analysis of the velocity field. The deconvolution approach is accurate in detecting vortex centers but cannot discriminate between vortices and high-shear regions. Therefore, this approach is combined with analysis of the Jacobian of the velocity field. Scale-space theory is used to evaluate aneurysmal flow velocity fields at various scales. Results: The proposed algorithm is applied to computational fluid dynamics and time-resolved 3-D phase-contrast magnetic resonance imaging of aneurysmal flow. Conclusion: Results show that the proposed algorithm efficiently detects, visualizes, and quantifies vortices in intracranial aneurysmal velocity patterns at multiple scales and follows the temporal evolution of these patterns. Significance: Quantitative analysis performed with this method has the potential to reduce interobserver variability in aneurysm classification.

Automatic Planning of Minimally Invasive Aortic Valve Replacement Surgery

The minimally invasive aortic valve replacement procedure provides a good alternative to conventional open heart surgery. Currently, Planning of the mini-AVR is supported by the selection of closest intercostal space to the sinutubular junction manually. In this work, we automate and standardize this planning by automatically detecting the intercostal spaces and the sinutubular junction, from which we calculate the closest incision location. The proposed algorithm provides qualitatively and quantitative accurate results; where the sinutubular junction detection has mean error of 3.4 mm. This work has the potential to be implemented in the clinical practice for reproducible and accurate mini-AVR planning.

Thrombospondin-4 mediates cardiovascular remodelling in angiotensin II-induced hypertension

Thrombospondin 4 (TSP-4) expression is induced in the heart and vasculature under pathological conditions, including myocardial infarction, myocardial pressure overload, and hypertension. TSP-4 is linked to remodelling processes, where it may affect extracellular matrix protein organization. In previous work, we studied the role of TSP-4 in small arteries during hypertension using Ang II-treated Thrombospondin 4 knockout (Thbs4-/-) mice. We reported increased heart weight, as well as the occurrence of aortic aneurysms in the Ang II-treated Thbs4-/- animals. In the present study, we further characterized the hearts and aortas from these animals. Hypertrophy of cardiomyocytes, together with perivascular fibrosis and inflammation was observed in the Ang II-treated Thbs4-/- hearts. In the aortas, an increase in the aortic wall cross-sectional area (CSA) and wall thickness of the Ang II-treated Thbs4-/- mice was found. More detailed investigation of the Ang II-treated Thbs4-/- aortas also revealed the appearance of aortic dissections in the outer medial layer of the arteries, as well as pronounced inflammation. No differences were found in several other extracellular matrix-related parameters, such as number of elastin breaks or stress-strain relationships. However, at the ultrastructural level, collagen fibers showed alterations in diameter in the media and adventitia of the Ang II-treated Thbs4-/- mice, in the area prone to dissection. In conclusion, we identified TSP-4 as an important protein in the development of cardiac hypertrophy and aortic dissections in Ang II-induced hypertension.