Investigating the Role of cAMP-Signaling in the Regulation of Vascular Endothelial Cell Adaptive Responses to Fluid Shear Stress

The circulating blood exerts a force on the vascular endothelium, termed fluid shear stress (FSS), which directly impacts numerous vascular endothelial cell (VEC) functions. For example, high rates of linear and undisturbed (i.e. laminar) blood flow maintains a protective and quiescent VEC phenotype. Meanwhile, deviations in blood flow, which can occur at vascular branchpoints and large curvatures, create areas of low, and/or oscillatory FSS, and promote a pro-inflammatory, pro-thrombotic and hyperpermeable phenotype. Indeed, it is known that these areas are prone to the development of atherosclerotic lesions. Herein, we show that cyclic nucleotide phosphodiesterase (PDE) 4D (PDE4D) activity is increased by FSS in human arterial endothelial cells (HAECs) and that this activation regulates the activity of cAMP-effector protein, Exchange Protein-activated by cAMP-1 (EPAC1), in these cells. Importantly, we also show that these events directly and critically impact HAEC responses to FSS, especially when FSS levels are low. Both morphological events induced by FSS, as measured by changes in cell alignment and elongation in the direction of FSS, and the expression of critical FSS-regulated genes, including Krüppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS) and thrombomodlin (TM), are mediated by EPAC1/PDE4D signaling. At a mechanistic level, we show that EPAC1/PDE4D acts through the vascular endothelial-cadherin (VECAD)/ platelet-cell adhesion molecule-1 (PECAM1)/vascular endothelial growth factor receptor 2 (VEGFR2) mechanosensor to activate downstream signaling though Akt. Given the critical role of PDE4D in mediating these effects, we also investigated the impact of various patterns of FSS on the expression of individual PDE genes in HAECs. Notably, PDE2A was significantly upregulated in response to high, laminar FSS, while PDE3A was upregulated under low, oscillatory FSS conditions only. These data may provide novel therapeutic targets to limit FSS-dependent endothelial cell dysfunction (ECD) and atherosclerotic development.

Current Challenges regarding the International Refugee Law, with focus on EU Policies and EU Co-operation with UNHCR. CEPS Paper on Liberty and Security in Europe No. 59, September 2013

From an examination of the instruments of the Common European Asylum System (CEAS) and related policy measures regarding border surveillance and migration management, two interrelated issues stand out as particularly sensitive: Access to asylum and responsibility for refugee protection. The prevailing view, supported by UNHCR and others, is that responsibility for the care of asylum seekers and the determination of their claims falls on the state within whose jurisdiction the claim is made. However, the possibility to shift that responsibility to another state through inter-state cooperation or unilateral mechanisms undertaken territorially as well as abroad has been a matter of great interest to EU Member States and institutions. Initiatives adopted so far challenge the prevailing view and have the potential to undermine compliance with international refugee and human rights law. This note reviews EU action in the field by reference to the relevant legal standards and best practices developed by UNHCR, focusing on the specific problems of climate refugees and access to international protection, evaluating the inconsistencies between the internal and external dimension of asylum policy. Some recommendations for the European Parliament are formulated at the end, including on action in relation to readmission agreements, Frontex engagement rules in maritime operations, Regional Protection Programmes, and resettlement.

Europe’s Double Refugee Crisis. CEPS Commentary, 8 September 2015

Against the background of the rapidly growing number of asylum-seekers, Daniel Gros argues in this CEPS Commentary that the EU needs to take action on two fronts. First, member countries must urgently boost their capacity to deal with asylum applications, so that they can quickly identify those who truly deserve protection. Second, the EU needs to improve burden-sharing in providing shelter for those who gain asylum. In his view, international law – and basic morality – demands nothing less.

Heads buried in the sand: member states block solutions to the refugee crisis. EPC Commentary, 15 September 2015

Yesterday’s meeting of Interior Ministers demonstrated that the EU’s asylum and immigration policy remains incomplete. This is mainly due to the member states’ inability to plan ahead, their reluctance to adopt binding common rules – considered as a violation of their sovereignty – and their central position in the implementation of EU rules.

Germany’s ‘refugee’ problem. The most important test for Chancellor Merkel and the grand coalition. OSW COMMENTARY NUMBER 182/11.09.2015 2015-09-11

The rapid increase in the number of immigrants from outside of the EU coming to Germany has become the paramount political issue. According to new estimates, the number of individuals expected arrive in Germany in 2015 and apply for asylum there is 800,000, which is nearly twice as many as estimated in earlier forecasts. Various administrative, financial and social problems related to the influx of migrants are becoming increasingly apparent. The problem of ‘refugees’ (in public debate, the terms ‘immigrants’, ‘refugees’, ‘illegal immigrants’, ‘economic immigrants’ have not been clearly defined and have often been used interchangeably) has been culminating for over a year. Despite this, it was being disregarded by Angela Merkel’s government which was preoccupied with debates on how to rescue Greece. It was only daily reports of cases of refugee centres being set on fire that convinced Chancellor Merkel to speak and to make immigration problem a priority issue (Chefsache). Neither the ruling coalition nor the opposition parties have a consistent idea of how Germany should react to the growing number of refugees. In this matter, divisions run across parties. Various solutions have been proposed, from liberalisation of laws on the right to stay in Germany to combating illegal immigration more effectively, which would be possible if asylum granting procedures were accelerated. The proposed solutions have not been properly thought through, instead they are reactive measures inspired by the results of opinion polls. This is why their assumptions are often contradictory. The situation is similar regarding the actions proposed by Chancellor Merkel which involve faster procedures to expel individuals with no right to stay in Germany and a plan to convince other EU states to accept ‘refugees’. None of these ideas is new – they were already present in the German internal debate.

The refugee crisis: Schengen’s slippery slope. EPC Commentary, 22 September 2015

While the European Union (EU) is facing one of the most divisive crises in its history, the pressure to take immediate action is enormous. Yet, negotiations in the Council have shown that the prospect of a common European response to the manifold effects and underlying reasons of the refugee crisis still belongs to the distant future. Only a few days after Commission President Jean-Claude Juncker delivered his State of the Union address – avowing that Schengen will not be abolished under his term – national decisions to reintroduce temporary border controls are multiplying. Germany, one of the most ardent defenders of a borderless Union, decided to temporarily reinstate border checks. Austria and Slovenia came next. Slovakia, the Czech Republic, Poland, the Netherlands and France might follow.

To adopt refugee quotas or not: Is that the question? CEPS Commentary, 2 October 2015

One of the most controversial initiatives taken by the EU in response to the recent influx of refugees has been a provisional relocation system, aimed at the distribution of 120,000 asylum-seekers from Greece and Italy to other EU member states. This commentary explores the flaws in the current Dublin system and evaluates whether the new approach will prove more effective and humane.