Primary cilia on endothelial cells : component of the shear stress sensor localized to athero-prone flow areas

Blood-flow-induced shear stress plays an important role in cardiovascular development and disease. How endothelial cells sense shear stress remains to be elucidated. We postulated that the primary cilium is a component of the endothelial shear sensor. This luminal cell protrusion contains microtubules and is connected to the microtubular cytoskeleton. We identified cilia on endothelial cells of the embryonic heart in areas of low or oscillatory shear stress. This shear-related distribution is reminiscent of the distribution of atherosclerotic lesions in the adult arterial system, as lesions develop at sites of low or oscillating shear (athero-prone flow). Ciliated endothelial cells are exclusively present at these atherosclerotic predilection sites in adult mice. Athero-prone (oscillatory) but not athero-protective (steady or pulsatile) flow induces ciliation of cultured endothelial cells. Moreover, the endothelial shear response is dependent on the microtubular cytoskeleton and primary cilia sensitise the endothelium for shear. Taken together, these data demonstrate that primary cilia are induced by athero-prone flow and that ciliated cells are more sensitive to shear stress. We conclude that the endothelial biosensor for shear stress is the microtubular cytoskeleton and that the attached primary cilium functions as a signal amplifier in areas subjected to athero-prone flow.UBL - phd migration 201

Metacognitieve therapie voor de obsessieve-compulsieve stoornis

De obsessieve-compulsieve stoornis (OCS) is een veelvoorkomende en invaliderende stoornis. Cognitieve gedragstherapie (CGT) in de vorm van exposure met responspreventie (ERP) is de psychologische behandeling van eerste voorkeur. Ondanks de aangetoonde werkzaamheid van ERP is verbetering van de effectivitei

Temporal and spatial changes in wall shear stress during atherosclerotic plaque progression in mice

Wall shear stress (WSS) is involved in atherosclerotic plaque initiation, yet its role in plaque progression remains unclear. We aimed to study (i) the temporal and spatial changes in WSS over a growing plaque and (ii) the correlation between WSS and plaque composition, using animal-specific data in an atherosclerotic mouse model. Tapered casts were placed around the right common carotid arteries (RCCA) of ApoE−/− mice. At 5, 7 and 9 weeks after cast placement, RCCA geometry was reconstructed using contrast-enhanced micro-CT. Lumen narrowing was observed in all mice, indicating the progression of a lumen intruding plaque. Next, we determined the flow rate in the RCCA of each mouse using Doppler Ultrasound and computed WSS at all time points. Over time, as the plaque developed and further intruded into the lumen, absolute WSS significantly decreased. Finally at week 9, plaque composition was histologically characterized. The proximal part of the plaque was small and eccentric, exposed to relatively lower WSS. Close to the cast a larger and concentric plaque was present, exposed to relatively higher WSS. Lower WSS was significantly correlated to the accumulation of macrophages in the eccentric plaque. When pooling data of all animals, correlation between WSS and plaque composition was weak and no longer statistically significant. In conclusion, our data showed that in our mouse model absolute WSS strikingly decreased during disease progression, which was significantly correlated to plaque area and macrophage content. Besides, our study demonstrates the necessity to analyse individual animals and plaques when studying correlations between WSS and plaque composition

Contrast-enhanced micro-CT imaging in murine carotid arteries: A new protocol for computing wall shear stress

Background: Wall shear stress (WSS) is involved in the pathophysiology of atherosclerosis. The correlation between WSS and atherosclerosis can be investigated over time using a WSS-manipulated atheroscleroti

Imaging inflammation in atherosclerotic plaques, targeting SST2 with [111In]In-DOTA-JR11

Background: Imaging Somatostatin Subtype Receptor 2 (SST2) expressing macrophages by [DOTA,Tyr3]-octreotate (DOTATATE) has proven successful for plaque detection. DOTA-JR11 is a SST2 targeting ligand with a five times higher tumor uptake than DOTATATE, and holds promise to improve plaque imaging. The aim of this study was to evaluate the potential of DOTA-JR11 for plaque detection. Methods and Results: Atherosclerotic ApoE−/− mice (n = 22) fed an atherogenic diet were imaged by SPECT/CT two hours post injection of [111In]In-DOTA-JR11 (~ 200 pmol, ~ 50 MBq). In vivo plaque uptake of [111In]In-DOTA-JR11 was visible in all mice, with a target-to-background-ratio (TBR) of 2.23 ± 0.35. Post-mortem scans after thymectomy and ex vivo scans of the arteries after excision of the arteries confirmed plaque uptake of the radioligand with TBRs of 2.46 ± 0.52 and 3.43 ± 1.45 respectively. Oil red O lipid-staining and ex vivo autoradiography of excised arteries showed [111In]In-DOTA-JR11 uptake at plaque locations. Histological processing showed CD68 (macrophages) and SST2 expressing cells in plaques. SPECT/CT, in vitro autoradiography and immunohistochemistry performed on slices of a human carotid endarterectomy sample showed [111In]In-DOTA-JR11 uptake at plaque locations containing CD68 and SST2 expressing cells. Conclusions: The results of this study indicate DOTA-JR1

The effect of the heart rate lowering drug Ivabradine on hemodynamics in atherosclerotic mice

The heart rate lowering drug Ivabradine was shown to improve cardiac outcome in patients with previous heart failure. However, in patients without heart failure, no beneficial effect of Ivabradine was observed. Animal studies suggested a preventive effect of Ivabradine on atherosclerosis which was due to an increase in wall shear stress (WSS), the blood flow-induced frictional force exerted on the endothelium, triggering anti-inflammatory responses. However, data on the effect of Ivabradine on WSS is sparse. We aim to study the effect of Ivabradine on (i) the 3D WSS distribution over a growing plaque and (ii) plaque composition. We induced atherosclerosis in ApoE−/− mice by placing a tapered cast around the right common carotid artery (RCCA). Five weeks after cast placement, Ivabradine was administered via drinking water (15 mg/kg/day) for 2 weeks, after which the RCCA was excised for histology analyses. Before and after Ivabradine treatment, animals were imaged with Doppler Ultrasound to measure blood velocity. Vessel geometry was obtained using contrast-enhanced micro-CT. Time-averaged WSS during systole, diastole and peak WSS was subsequently computed. Ivabradine significantly decreased heart rate (459 ± 28 bpm vs. 567 ± 32 bpm, p < 0.001). Normalized peak flow significantly increased in the Ivabradine group (124.2% ± 40.5% vs. 87.3% ± 25.4%, p < 0.05), reflected by an increased normalized WSS level during systole (110.7% ± 18.4% vs. 75.4% ± 24.6%, p < 0.05). However, plaque size or composition including plaque area, relative necrotic core area and macrophage content were not altered in mice treated with Ivabradine compared to controls. We conclude that increased WSS in response to Ivabradine treatment did not affect plaque progression in a murine model

Metacognitive therapy versus exposure and response prevention for obsessive-compulsive disorder

Background: The recommended psychological treatment of choice for obsessive-compulsive disorder (OCD) is exposure with response prevention (ERP). However, recovery rates are relatively modest, so better treatments are needed. This superiority study aims to explore the relative efficacy of metacognitive therapy (MCT), a new form of cognitive therapy based on the metacognitive model of OCD. Design and method: In a randomized controlled trial, we will compare MCT with ERP. One hundred patients diagnosed with OCD will be recruited in an outpatient mental health center in Rotterdam (the Netherlands). The primary outcome measure is OCD severity, measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Data are assessed at baseline, after treatment, and at 6 and 30 months follow-up. Discussion: By comparing MCT with ERP we hope to provide an indication whether MCT is efficacious in the treatment of OCD and, if so, whether it has the potential to be more efficacious than the current “gold standard” psychological treatment for OCD, ERP