Maria Schiller

Esm1 Modulates Endothelial Tip Cell Behavior and Vascular Permeability by Enhancing VEGF Bioavailability

Rationale: Endothelial cell–specific molecule 1 (Esm1) is a secreted protein thought to play a role in angiogenesis and inflammation. However, there is currently no direct in vivo evidence supporting a function of Esm1 in either of these processes. Objective: To determine the role of Esm1 in vivo and the underlying molecular mechanisms. Methods and Results: We generated and analyzed Esm1 knockout (Esm1KO) mice to study its role in angiogenesis and inflammation. Esm1 expression is induced by the vascular endothelial growth factor A (VEGF-A) in endothelial tip cells of the mouse retina. Esm1KO mice showed delayed vascular outgrowth and reduced filopodia extension, which are both VEGF-A–dependent processes. Impairment of Esm1 function led to a decrease in phosphorylated Erk1/2 (extracellular-signal regulated kinases 1/2) in sprouting vessels. We also found that Esm1KO mice displayed a 40% decrease in leukocyte transmigration. Moreover, VEGF-induced vascular permeability was decreased by 30% in Esm1KO mice and specifically on stimulation with VEGF-A165 but not VEGF-A121. Accordingly, cerebral edema attributable to ischemic stroke–induced vascular permeability was reduced by 50% in the absence of Esm1. Mechanistically, we show that Esm1 binds directly to fibronectin and thereby displaces fibronectin-bound VEGF-A165 leading to increased bioavailability of VEGF-A165 and subsequently enhanced levels of VEGF-A signaling. Conclusions: Esm1 is simultaneously a target and modulator of VEGF signaling in endothelial cells, playing a role in angiogenesis, inflammation, and vascular permeability, which might be of potential interest for therapeutic applications.

Blood flow controls bone vascular function and osteogenesis

While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood. Here we show that the long bone vasculature generates a peculiar flow pattern, which is important for proper angiogenesis. Intravital imaging reveals that vessel growth in murine long bone involves the extension and anastomotic fusion of endothelial buds. Impaired blood flow leads to defective angiogenesis and osteogenesis, and downregulation of Notch signalling in endothelial cells. In aged mice, skeletal blood flow and endothelial Notch activity are also reduced leading to decreased angiogenesis and osteogenesis, which is reverted by genetic reactivation of Notch. Blood flow and angiogenesis in aged mice are also enhanced on administration of bisphosphonate, a class of drugs frequently used for the treatment of osteoporosis. We propose that blood flow and endothelial Notch signalling are key factors controlling ageing processes in the skeletal system.

Paradigmatic pragmatism and the politics of diversity

How migration and mobilizations of difference are accommodated at the local level is a burning question. Concepts adopted by local governments and the capacities of cities to formulate and implement these have received increasing attention, but often without examining the ideas and norms that underlie local concepts and practices. This article assesses the hypothesis of local-level pragmatism, which it rejects, and develops the notion of ‘paradigmatic pragmatism’ to characterize how local-level politics address mobilizations of difference. Based on empirical findings from Amsterdam, Antwerp and Leeds, and comparing the content and the implementation of ‘diversity policies’, I argue against a dichotomy of pragmatic vs ideational politics. Instead, these cities draw on a variety of ideas and pragmatically combine them under the header of diversity. This paradigmatic pragmatism invites further research on the effects of potential incompatibilities of immigrant policy ideas.

The implementation trap: the local level and diversity policies

There is widespread agreement that the local level has become more self-confident and self-reliant in formulating its own immigrant policies and sometimes developing distinct philosophies of immigrant incorporation. However, to date we know little about the actual capacities of cities to implement these philosophies consistently. This article offers a level-specific study of the governance of immigrant incorporation by European municipalities. It focuses on cities with diversity policies and it compares the meaning of diversity in formulated policies with policy implementation. Identifying an implementation gap of diversity policies in Antwerp, Amsterdam and Leeds, it argues that cities may have become more self-reliant and self-confident in coming up with their own ideas and concepts for governing immigration, but this may not mean that they also consistently implement these ideas. This article identifies two explanations for an implementation gap and different capacities across cities to consistently implement such policies. Points for practitioners The article establishes two explanations for the inconsistent implementation of policies, focusing on the case of local diversity policies, and delineates how this plays out across different cities. These findings are relevant as they allow us to define the conditions for consistent policy implementation.

Authenticity or skill-oriented individualism, neutrality or managerialism: diversity officers as modern public officials

ABSTRACT Diversity has become a new buzzword in European cities. Newly introduced diversity policies have replaced previous multicultural policies with an approach that acknowledges difference in a more general sense. Drawing on in-depth fieldwork in diversity departments in Amsterdam, Antwerp and Leeds, this article investigates how the introduction of diversity policy impacted on the recruitment and the self-representations of public officials in newly created diversity departments. Despite a proclaimed move away from recognising minority-group specificities, many officials conceive their immigrant origin as a central element of their profiles. This continuation of a multicultural logic is interpreted as misunderstanding or resistance on the part of those meant to implement these policies, indicating agency of contemporary bureaucrats as well as creative space within bureaucracies. In order to place the shift from multicultural to diversity policy in the context of welfare state transformation and neoliberalism, I assess whether diversity officers endorse diversity policies in conjunction with New Public Management policies. However, I do not find an unequivocal promotion of both policies and my study thus does not confirm the common association of diversity policies with neoliberalism.

Economy or Justice? How Urban Actors Respond to Diversity:

The diversification of population, demands for recognition, and the spread of diversity policies present new challenges to European cities. Do urban actors respond to this development in different ways across cities? Can we distinguish a logic determined by economic considerations or rather a justice-oriented logic? This article presents evidence from 20 German cities based on an original survey of important urban actors. This design reflects current realities of urban governance. Results indicate that, across Germany’s biggest cities, there is a normative consensus over the benefits of diversity. However, other positions are controversial and views seem partly incoherent. Cities neither clearly position themselves as pro- or antidiversity cities nor do most of them adopt clear market-oriented or justice-oriented approaches. We conclude that, in a relatively new field, positions are still uncrystallized, and hybrid combinations of perspectives may remain typical in societies with strong social-welfare traditions.

Continuity and change in local immigrant policies in times of austerity

European cities are increasingly being recognised for the role they play in devising and implementing their own migration, integration and diversity policies. Yet very little is known about the local dimension of immigrant policymaking in crisis contexts. This introductory piece offers a rationale for analysing city-level immigrant policies in times of crisis and the salience of using crisis as a metaphor for the state of things, and outlines key scholarly works, debates, concepts and theories. It provides a range of historical and contemporary examples and considerations, and introduces an empirical city case study that is published as part of this mini-symposium. It argues that a crisis lens leads to a systematic understanding of local-level immigrant policymaking in recent and contemporary Western Europe. The mini-symposium’s focus and findings should be relevant to both on-going academic and policy debates.

Diversity Policy in Practice

What are the different triggers for and shared definitions of diversity policies in Amsterdam, Antwerp, and Leeds? How are departments being reshaped to implement diversity policies, and how are they located within local bureaucratic organizations? How do local authorities recruit the bureaucrats who are then put in charge of implementing diversity policies? And how do the practices of these bureaucrats reflect the shared definition of diversity policies? This chapter develops my argument that a politics of diversity depends not only on the underlying political concepts, but also on the dispositions of the officials who interpret these concepts in their work.

Paradigmatic pragmatism: The Character of Local Responses to Difference

This chapter presents the core finding of this book: Local diversity policies pragmatically combine some new ideas on how to approach mobilizations of change in difference as well as some preceding ideas from earlier ‘minorities’ or ‘equality’ policies. It presents such evidence by analyzing the activities conducted under the header of diversity and identifies the ideas they are inspired by. Rather than continuing with the same policies under a new label or wholeheartedly replacing earlier politics with a new approach, we find that ‘diversity’ in fact is a container concept for promoting different approaches to difference simultaneously. Different activities reflect a range of policy ideas and are inspired by paradigms of multiculturalism, assimilation, and diversity. The chapter crystallizes what kind of politics can be found under the header of diversity in European cities, and thereby answers the central question of this study.

The Changing Nature of Public Authorities and Bureaucrats

This chapter explains why and how public authorities and bureaucrats play a role in governing local mobilizations of difference. It demonstrates how trends of modernization and diversification have redefined the profile of local bureaucrats, who are today subject to expectations of entrepreneurialism and authenticity. These new expectations reshape the profile of the public official, which we find reflected in recruitment strategies as well as in their diverse self-representations.