Lymphatic vessels in health and disease: Role of the VEGF-C/VEGFR-3 pathway and the transcription factor FOXC2

The circulatory system consists of two vessel types, which act in concert but significantly differ from each other in several structural and functional aspects as well as in mechanisms governing their development. The blood vasculature transports oxygen, nutrients and cells to tissues whereas the lymphatic vessels collect extravasated fluid, macromolecules and cells of the immune system and return them back to the blood circulation. Understanding the molecular mechanisms behind the developmental and functional regulation of the lymphatic system long lagged behind that of the blood vasculature. Identification of several markers specific for the lymphatic endothelium, and the discovery of key factors controlling the development and function of the lymphatic vessels have greatly facilitated research in lymphatic biology over the past few years. Recognition of the crucial importance of lymphatic vessels in certain pathological conditions, most importantly in tumor metastasis, lymphedema and inflammation, has increased interest in this vessel type, for so long overshadowed by its blood vascular cousin. VEGF-C (Vascular Endothelial Growth Factor C) and its receptor VEGFR-3 are essential for the development and maintenance of embryonic lymphatic vasculature. Furthermore, VEGF-C has been shown to be upregulated in many tumors and its expression found to positively correlate with lymphatic metastasis. Mutations in the transcription factor FOXC2 result in lymphedema-distichiasis (LD), which suggests a role for FOXC2 in the regulation of lymphatic development or function. This study was undertaken to obtain more information about the role of the VEGF-C/VEGFR-3 pathway and FOXC2 in regulating lymphatic development, growth, function and survival in physiological as well as in pathological conditions. We found that the silk-like carboxyterminal propeptide is not necessary for the lymphangiogenic activity of VEGF-C, but enhances it, and that the aminoterminal propeptide mediates binding of VEGF-C to the neuropilin-2 coreceptor, which we suggest to be involved in VEGF-C signalling via VEGFR-3. Furthermore, we found that overexpression of VEGF-C increases tumor lymphangiogenesis and intralymphatic tumor growth, both of which could be inhibited by a soluble form of VEGFR-3. These results suggest that blocking VEGFR-3 signalling could be used for prevention of lymphatic tumor metastasis. This might prove to be a safe treatment method for human cancer patients, since inhibition of VEGFR-3 activity had no effect on the normal lymphatic vasculature in adult mice, though it did lead to regression of lymphatic vessels in the postnatal period. Interestingly, in contrast to VEGF-C, which induces lymphangiogenesis already during embryonic development, we found that the related VEGF-D promotes lymphatic vessel growth only after birth. These results suggest, that the lymphatic vasculature undergoes postnatal maturation, which renders it independent of ligand induced VEGFR-3 signalling for survival but responsive to VEGF-D for growth. Finally, we show that FOXC2 is necessary for the later stages of lymphatic development by regulating the morphogenesis of lymphatic valves, as well as interactions of the lymphatic endothelium with vascular mural cells, in which it cooperates with VEGFR-3. Furthermore, our study indicates that the absence of lymphatic valves, abnormal association of lymphatic capillaries with mural cells and an increased amount of basement membrane underlie the pathogenesis of LD. These findings have given new insight into the mechanisms of normal lymphatic development, as well as into the pathogenesis of diseases involving the lymphatic vasculature. They also reveal new therapeutic targets for the prevention and treatment of tumor metastasis and lymphatic vascular failure in certain forms of lymphedema. Several interesting questions were posed that still need to be addressed. Most importantly, the mechanism of VEGF-C promoted tumor metastasis and the molecular nature of the postnatal lymphatic vessel maturation remain to be elucidated.

The Pathobiology of the Saccular Cerebral Artery Aneurysm Rupture and Repair : A Clinicopathological and Experimental Approach

Backround and Purpose The often fatal (in 50-35%) subarachnoid hemorrhage (SAH) caused by saccular cerebral artery aneurysm (SCAA) rupture affects mainly the working aged population. The incidence of SAH is 10-11 / 100 000 in Western countries and twice as high in Finland and Japan. The estimated prevalence of SCAAs is around 2%. Many of those never rupture. Currently there are, however, no diagnostic methods to identify rupture-prone SCAAs from quiescent, (dormant) ones. Finding diagnostic markers for rupture-prone SCAAs is of primary importance since a SCAA rupture has such a sinister outcome, and all current treatment modalities are associated with morbidity and mortality. Also the therapies that prevent SCAA rupture need to be developed to as minimally invasive as possible. Although the clinical risk factors for SCAA rupture have been extensively studied and documented in large patient series, the cellular and molecular mechanisms how these risk factors lead to SCAA wall rupture remain incompletely known. Elucidation of the molecular and cellular pathobiology of the SCAA wall is needed in order to develop i) novel diagnostic tools that could identify rupture-prone SCAAs or patients at risk of SAH, and to ii) develop novel biological therapies that prevent SCAA wall rupture. Materials and Methods In this study, histological samples from unruptured and ruptured SCAAs and plasma samples from SCAA carriers were compared in order to identify structural changes, cell populations, growth factor receptors, or other molecular markers that would associate with SCAA wall rupture. In addition, experimental saccular aneurysm models and experimental models of mechanical vascular injury were used to study the cellular mechanisms of scar formation in the arterial wall, and the adaptation of the arterial wall to increased mechanical stress. Results and Interpretation Inflammation and degeneration of the SCAA wall, namely loss of mural cells and degradation of the wall matrix, were found to associate with rupture. Unruptured SCAA walls had structural resemblance with pads of myointimal hyperplasia or so called neointima that characterizes early atherosclerotic lesions, and is the repair and adaptation mechanism of the arterial wall after injury or increased mechanical stress. As in pads of myointimal hyperplasia elsewhere in the vasculature, oxidated LDL was found in the SCAA walls. Immunity against OxLDL was demonstrated in SAH patients with detection of circulating anti-oxidized LDL antibodies, which were significantly associated with the risk of rupture in patients with solitary SCAAs. Growth factor receptors associated with arterial wall remodeling and angiogenesis were more expressed in ruptured SCAA walls. In experimental saccular aneurysm models, capillary growth, arterial wall remodeling and neointima formation were found. The neointimal cells were shown to originate from the experimental aneurysm wall with minor contribution from the adjacent artery, and a negligible contribution of bone marrow-derived neointimal cells. Since loss of mural cells characterizes ruptured human SCAAs and likely impairs the adaptation and repair mechanism of ruptured or rupture-prone SCAAs, we investigated also the hypothesis that bone marrow-derived or circulating neointimal precursor cells could be used to enhance neointima formation and compensate the impaired repair capacity in ruptured SCAA walls. However, significant contribution of bone marrow cells or circulating mononuclear cells to neointima formation was not found.

Käsitteellisestä ruumiilliseen, sitaatiosta paikkaan - maalaustaide ja nykytaiteen historia

The dissertation "From Conceptual to Corporeal, from Quotation to Site: Painting and History of Contemporary Art" explores the state of painting in contemporary art and art theory since the 1960s. The purpose of the study is to re-consider the dominant "end of painting" -narrative in contemporary art history, which goes back to the modernist ideology of painting as a reductive, medium-specific form of art. Drawing on Michel Foucault´s concepts of discursive formation and archive, as well as Jean-Luc Nancy´s post-phenomenological philosophy on corporeality, I suggest that contemporary painting can be redefined as a discursive-sensuous practice. Instead of seeing painting as obsolete or over as an avantgarde art genre, I show that there have been alternative, neo-avantgardist ways of defining painting since the end of the 1960s, such as French artist Daniel Buren´s early writings on painting as "theoretical practice". Consequently, the tendency of the canonical Anglo-American contemporary art narratives to underestimate the historical and institutional codes of art can be questioned. This tendency can be seen, for example, in Rosalind Krauss´s influential theory on index. The study also reflects the relations between conceptual art and painting since the 1960s and maps recent theories of painting, which re-examine the genre´s possibilities after the modernist rhetoric. Concepts of "flatbed", "painting in the extended field", "as painting" and so on are compared critically with the idea of painting as discursive practice. It is also shown that the issues in painting arise from the contemporary critical art debate while the dematerialisation paradigm of conceptual art has dissolved. The study focuses on the corporeal-material-sensuous -cluster of meanings attached to painting and searches for its avantgardist possibilities as redefined by postfeminist and post-phenomenological discourse. The ideas of hierarchy of the senses and synesthesia are developed within the framework of Jean-Luc Nancy´s and Luce Irigaray´s thought. The parameters for the study have been Finnish painting from 1990 to 2002. On the Finnish art scene there has been no "end of painting" ideology, strictly speaking. The mythology and medium-specificity of modernism have been deconstructed since the mid-1980s, but "the archive" of painting, like themes of abstraction, formalism and synesthesia have been re-worked by the discursive practice of painting, for example, in the works of Nina Roos, Tarja Pitkänen-Walter and Jussi Niva.

Aktiiviseen kansalaisuuteen kasvattaminen yläkoulun maantieteen opetuksessa

Tutkielmassa tarkasteltiin aktiivista kansalaisuutta perusopetuksen yläkoulun (luokat 7–9) maantieteen opetuksessa. Tutkielman taustana olivat aktiiviseen kansalaisuuteen liittyvät viralliset ja epäviralliset diskurssit: opetussuunnitelman perusteiden aihekokonaisuudet, kouluun kohdistuvat kansalaiskasvatushankkeet sekä nuoriin, kansalaisuuteen ja kansalaisyhteiskuntaan liittyvät keskustelut. Maantieteen opetuksen osalta taustana olivat opetussuunnitelman velvoitteet huomioida aktiivinen kansalaisuus yläkoulun maantieteen opetuksessa sekä (pääasiassa brittiläinen) kirjallisuus, jossa maantieteen ja kansalaiskasvatuksen/aktiivisen kansalaisuuden välillä nähdään yhtäläisyyksiä. Tutkielmassa pyrittiin selvittämään, mitä aktiivinen kansalaisuus on yläkoulun maantieteen opetuksessa ja miten maantieteen opettajat suhtautuvat tehtäviinsä nuorten kansalaisten kasvattajina ja yhteiskunnallisina vaikuttajina. Tutkielmaa varten kerättiin teemahaastatteluaineisto kuudelta yläkoulun maantieteen opettajalta. Haastatteluihin pyrittiin löytämään mahdollisimman aktiivisia maantieteen opettajia. Haastatteluaineiston analyysissa käytettiin sisällönanalyysia, ja aineiston avulla pyrittiin kuvaamaan ilmiötä. Haastateltujen opettajien mukaan yläkoulun maantieteen opetuksessa luonnonmaantieteelliset sisällöt painottuvat enemmän kuin kulttuurimaantieteelliset. Aktiivisen kansalaisuuden kannalta keskeisiä sisältöjä, kuten vaikutusmahdollisuuksia oman ympäristön suunnitteluun ja kehittymiseen sekä kotikunnan ja lähiympäristön tutkimista käsitellään opetuksessa vain vähän, jos ollenkaan. Aktiivinen kansalaisuus on yläkoulun maantieteen opetuksessa eniten tiedon jakamista, ajattelun taitojen ja mielipiteen muodostamisen harjoittelua sekä ympäristövastuullisuuteen kansalaisuuteen kasvattamista. Opetuksessa käytetään myös aktiivisen kansalaisuuden kannalta keskeisiä työtapoja, mutta työtapojen käyttö vaihtelee. Haastatellut opettajat eivät koe opetussuunnitelman aihekokonaisuuksia juurikaan omakseen. Opettajat eivät myöskään määrittele kansalaisvaikuttamiseen kasvattamista koulun tärkeimpien tehtävien joukkoon. Osa opettajista kokee kuitenkin olevansa yhteiskunnallinen vaikuttaja opettajana. Opettajien puheessa koulun kansalaiskasvatuksen tavoite, kunnon kansalainen, ei määrity kovin aktiivisena tai poliittisena. Opettajien puhe sisältää kuitenkin monenlaisia näkemyksiä suhteessa nuoriin kansalaisina ja aktiivisuuteen: toisaalta nuoret eivät ole kiinnostuneita yhteiskunnallisista asioista eikä heiltä vaaditakaan sitä, toisaalta maaperä nuorten kasvattamiseen aktiivisiksi kansalaisiksi on hyvä ja aktiivisuus on pieniä asioita lähiympäristössä sekä yhdessä tekemiseen uskomista. Haastattelujen pohjalta todettiin, että lukuun ottamatta joidenkin opettajien ympäristökasvatuksellista otetta, aktiivinen kansalaisuus ei ole täysin tiedostettu tavoite yläkoulun maantieteen opetuksessa.

Multiple socioeconomic circumstances and health : associations and explanations among Finnish and British public sector employees

Socioeconomic health inequalities have been widely documented, with a lower social position being associated with poorer physical and general health and higher mortality. For mental health the results have been more varied. However, the mechanisms by which the various dimensions of socioeconomic circumstances are associated with different domains of health are not yet fully understood. This is related to a lack of studies tackling the interrelations and pathways between multiple dimensions of socioeconomic circumstances and domains of health. In particular, evidence from comparative studies of populations from different national contexts that consider the complexity of the causes of socioeconomic health inequalities is needed. The aim of this study was to examine the associations of multiple socioeconomic circumstances with physical and mental health, more specifically physical functioning and common mental disorders. This was done in a comparative setting of two cohorts of white-collar public sector employees, one from Finland and one from Britain. The study also sought to find explanations for the observed associations between economic difficulties and health by analysing the contribution of health behaviours, living arrangements and work-family conflicts. The survey data were derived from the Finnish Helsinki Health Study baseline surveys in 2000-2002 among the City of Helsinki employees aged 40-60 years, and from the fifth phase of the London-based Whitehall II study (1997-9) which is a prospective study of civil servants aged 35-55 years at the time of recruitment. The data collection in the two countries was harmonised to safeguard maximal comparability. Physical functioning was measured with the Short Form (SF-36) physical component summary and common mental disorders with the General Health Questionnaire (GHQ-12). Socioeconomic circumstances were parental education, childhood economic difficulties, own education, occupational class, household income, housing tenure, and current economic difficulties. Further explanatory factors were health behaviours, living arrangements and work-family conflicts. The main statistical method used was logistic regression analysis. Analyses were conducted separately for the two sexes and two cohorts. Childhood and current economic difficulties were associated with poorer physical functioning and common mental disorders generally in both cohorts and sexes. Conventional dimensions of socioeconomic circumstances i.e. education, occupational class and income were associated with physical functioning and mediated each other’s effects, but in different ways in the two cohorts: education was more important in Helsinki and occupational class in London. The associations of economic difficulties with health were partly explained by work-family conflicts and other socioeconomic circumstances in both cohorts and sexes. In conclusion, this study on two country-specific cohorts confirms that different dimensions of socioeconomic circumstances are related but not interchangeable. They are also somewhat differently associated with physical and mental domains of health. In addition to conventionally measured dimensions of past and present socioeconomic circumstances, economic difficulties should be taken into account in studies and attempts to reduce health inequalities. Further explanatory factors, particularly conflicts between work and family, should also be considered when aiming to reduce inequalities and maintain the health of employees.