| 1. |
- Enge, Maria, 1970, et al.
(författare)
-
Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy.
- 2002
-
Ingår i: The EMBO journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 21:16, s. 4307-16
-
Tidskriftsartikel (refereegranskat)abstract
- Loss of pericytes from the capillary wall is a hallmark of diabetic retinopathy, however, the pathogenic significance of this phenomenon is unclear. In previous mouse gene knockout models leading to pericyte deficiency, prenatal lethality has so far precluded analysis of postnatal consequences in the retina. We now report that endothelium-restricted ablation of platelet-derived growth factor-B generates viable mice with extensive inter- and intra-individual variation in the density of pericytes throughout the CNS. We found a strong inverse correlation between pericyte density and the formation of a range of retinal microvascular abnormalities strongly reminiscent of those seen in diabetic humans. Proliferative retinopathy invariably developed when pericyte density was <50% of normal. Our data suggest that a reduction of the pericyte density is sufficient to cause retinopathy in mice, implying that pericyte loss may also be a causal pathogenic event in human diabetic retinopathy.
|
|
| 2. |
- Axelsson, Kristian F, 1973, et al.
(författare)
-
Eating disorders are associated with increased risk of fall injury and fracture in Swedish men and women
- 2022
-
Ingår i: Osteoporosis International. - : Springer Science and Business Media LLC. - 0937-941X .- 1433-2965. ; 33, s. 1347-1355
-
Tidskriftsartikel (refereegranskat)abstract
- A Summary In this retrospective cohort study, men and women with eating disorders (n = 8867) had higher risk of injurious falls and hip fractures than age, sex, and county-matched controls (n = 88670). Introduction Eating disorders have been associated with decreased bone mineral density and increased fracture risk, but the association with fall injuries without fracture has not previously been investigated. Furthermore, fracture risk in men with eating disorders has been insufficiently studied. Methods In the present study, 8867 patients (9.4% men) with a diagnosed eating disorders and 88670 age-, sex-, and county-matched controls were investigated. Results The mean (standard deviation) age of the patients and controls was 41.6 (13.7) years and the follow-up time 9.6 (5.2, 14.4) years (median, interquartile range) for patients and 10.1 (5.5, 14.2) years for controls. The proportions of injurious falls without fracture (17.3% vs. 9.0%) and of hip fracture (1.6% vs. 0.7%) were substantially greater in patients with an eating disorder than in their corresponding population controls. In an unadjusted Cox proportional hazards model, individuals with an eating disorder had a higher risk of injurious falls without fracture (Hazard ratio (HR) 95% confidence interval (CI): 2.07 (1.96-2.18), and hip fracture (HR 2.30 (1.92-2.75)) than the risk observed in the controls. The HR for any investigated outcome associated with an eating disorder did not differ by sex or age (interaction term p > 0.10). The risk of injurious falls without fracture and hip fracture was increased in both women (HR 2.07 (1.95-2.19) and HR 2.41 (1.98-2.93), respectively) and men (HR 2.09 (1.76-2.49) and HR 1.84(1.12-3.02), respectively), with an eating disorder. Conclusion The risk of injurious falls without fracture and of hip fracture is increased in both women and men with eating disorders, indicating measures to prevent both falls and fractures are important in these patients, regardless of age and
|
|
| 3. |
- Bondjers, Cecilia, 1974, et al.
(författare)
-
Transcription profiling of platelet-derived growth factor-B-deficient mouse embryos identifies RGS5 as a novel marker for pericytes and vascular smooth muscle cells.
- 2003
-
Ingår i: The American journal of pathology. - 0002-9440. ; 162:3, s. 721-9
-
Tidskriftsartikel (refereegranskat)abstract
- All blood capillaries consist of endothelial tubes surrounded by mural cells referred to as pericytes. The origin, recruitment, and function of the pericytes is poorly understood, but the importance of these cells is underscored by the severe cardiovascular defects in mice genetically devoid of factors regulating pericyte recruitment to embryonic vessels, and by the association between pericyte loss and microangiopathy in diabetes mellitus. A general problem in the study of pericytes is the shortage of markers for these cells. To identify new markers for pericytes, we have taken advantage of the platelet-derived growth factor (PDGF)-B knockout mouse model, in which developing blood vessels in the central nervous system are almost completely devoid of pericytes. Using cDNA microarrays, we analyzed the gene expression in PDGF-B null embryos in comparison with corresponding wild-type embryos and searched for down-regulated genes. The most down-regulated gene present on our microarray was RGS5, a member of the RGS family of GTPase-activating proteins for G proteins. In situ hybridization identified RGS5 expression in brain pericytes, and in pericytes and vascular smooth muscle cells in certain other, but not all, locations. Absence of RGS5 expression in PDGF-B and PDGFR beta-null embryos correlated with pericyte loss in these mice. Residual RGS5 expression in rare pericytes suggested that RGS5 is a pericyte marker expressed independently of PDGF-B/R beta signaling. With RGS5 as a proof-of-principle, our data demonstrate the usefulness of microarray analysis of mouse models for abnormal pericyte development in the identification of new pericyte-specific markers.
|
|
| 4. |
- Felton, Adam, et al.
(författare)
-
Keeping pace with forestry : Multi-scale conservation in a changing production forest matrix
- 2020
-
Ingår i: Ambio. - : Springer. - 0044-7447 .- 1654-7209. ; 49:5, s. 1050-1064
-
Tidskriftsartikel (refereegranskat)abstract
- The multi-scale approach to conserving forest biodiversity has been used in Sweden since the 1980s, a period defined by increased reserve area and conservation actions within production forests. However, two thousand forest-associated species remain on Sweden's red-list, and Sweden's 2020 goals for sustainable forests are not being met. We argue that ongoing changes in the production forest matrix require more consideration, and that multi-scale conservation must be adapted to, and integrated with, production forest development. To make this case, we summarize trends in habitat provision by Sweden's protected and production forests, and the variety of ways silviculture can affect biodiversity. We discuss how different forestry trajectories affect the type and extent of conservation approaches needed to secure biodiversity, and suggest leverage points for aiding the adoption of diversified silviculture. Sweden's long-term experience with multi-scale conservation and intensive forestry provides insights for other countries trying to conserve species within production landscapes.
|
|
| 5. |
- Heiss, Maximilian, et al.
(författare)
-
Endothelial cell spheroids as a versatile tool to study angiogenesis in vitro
- 2015
-
Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 29:7, s. 3076-3084
-
Tidskriftsartikel (refereegranskat)abstract
- Given the need for robust and cost-efficient in vitro models to study angiogenesis and reproducibly analyze potential pro-and antiangiogenic compounds in preclinical studies, we developed a 3-dimensional in vitro angiogenesis assay that is based on collagen gel-embedded, size-defined spheroids generated from cultured human umbilical vein endothelial cells (HUVECs). Despite its wide distribution, limitations, sensitivity, robustness, and improvements, the capacity of this assay for functional screening purposes has not been elucidated thus far. By using time-lapse video microscopy, we show that tip cells lead the formation of capillary-like and partially lumenized sprouts originating from the spheroids. Angiogenic sprouting from spheroids generated from 5 different primary cultured human endothelial cell types was induced by physiologic concentrations of vascular endothelial cell growth factor 165. Based on this assay system, we determined the capacity of 880 approved drugs to interfere with or boost angiogenic sprouting, thereby assessing their putative angiogenesis-related side effects or novel applications. However, although this assay allowed for a rapid and reproducible determination of functional IC50 values of individual compounds, the sprouting results were partially affected by the HUVEC passage number and donor variability. To overcome this limitation, immortalized HUVECs (iHUVECs) showing a more homogenous response in terms of proliferation and sprouting over multiple population doublings were used in the course of this study. Collectively, the spheroid-based angiogenesis assay provides a sensitive and versatile tool to study the impact of pro-and antiangiogenic determinants on multiple steps of the angiogenic cascade. It is compatible with different endothelial cell types and allows use of iHUVECs to improve its overall robustness.
|
|
| 6. |
- Hellström, Mats, et al.
(författare)
-
Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis.
- 2007
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 445:7129, s. 776-80
-
Tidskriftsartikel (refereegranskat)abstract
- In sprouting angiogenesis, specialized endothelial tip cells lead the outgrowth of blood-vessel sprouts towards gradients of vascular endothelial growth factor (VEGF)-A. VEGF-A is also essential for the induction of endothelial tip cells, but it is not known how single tip cells are selected to lead each vessel sprout, and how tip-cell numbers are determined. Here we present evidence that delta-like 4 (Dll4)-Notch1 signalling regulates the formation of appropriate numbers of tip cells to control vessel sprouting and branching in the mouse retina. We show that inhibition of Notch signalling using gamma-secretase inhibitors, genetic inactivation of one allele of the endothelial Notch ligand Dll4, or endothelial-specific genetic deletion of Notch1, all promote increased numbers of tip cells. Conversely, activation of Notch by a soluble jagged1 peptide leads to fewer tip cells and vessel branches. Dll4 and reporters of Notch signalling are distributed in a mosaic pattern among endothelial cells of actively sprouting retinal vessels. At this location, Notch1-deleted endothelial cells preferentially assume tip-cell characteristics. Together, our results suggest that Dll4-Notch1 signalling between the endothelial cells within the angiogenic sprout serves to restrict tip-cell formation in response to VEGF, thereby establishing the adequate ratio between tip and stalk cells required for correct sprouting and branching patterns. This model offers an explanation for the dose-dependency and haploinsufficiency of the Dll4 gene, and indicates that modulators of Dll4 or Notch signalling, such as gamma-secretase inhibitors developed for Alzheimer's disease, might find usage as pharmacological regulators of angiogenesis.
|
|
| 7. |
- Kalén, Mattias, et al.
(författare)
-
Combination of reverse and chemical genetic screens reveals angiogenesis inhibitors and targets.
- 2009
-
Ingår i: Chemistry & biology. - : Elsevier BV. - 1879-1301 .- 1074-5521. ; 16:4, s. 432-41
-
Tidskriftsartikel (refereegranskat)abstract
- We combined reverse and chemical genetics to identify targets and compounds modulating blood vessel development. Through transcript profiling in mice, we identified 150 potentially druggable microvessel-enriched gene products. Orthologs of 50 of these were knocked down in a reverse genetic screen in zebrafish, demonstrating that 16 were necessary for developmental angiogenesis. In parallel, 1280 pharmacologically active compounds were screened in a human cell-based assay, identifying 28 compounds selectively inhibiting endothelial sprouting. Several links were revealed between the results of the reverse and chemical genetic screens, including the serine/threonine (S/T) phosphatases ppp1ca, ppp1cc, and ppp4c and an inhibitor of this gene family; Endothall. Our results suggest that the combination of reverse and chemical genetic screens, in vertebrates, is an efficient strategy for the identification of drug targets and compounds that modulate complex biological systems, such as angiogenesis.
|
|
| 8. |
- Kalén, Mattias, et al.
(författare)
-
Gamma-Secretase Inhibitor Treatment Promotes VEGF-A-Driven Blood Vessel Growth and Vascular Leakage but Disrupts Neovascular Perfusion
- 2011
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4, s. e18709-
-
Tidskriftsartikel (refereegranskat)abstract
- The Notch signaling pathway is essential for normal development due to its role in control of cell differentiation, proliferation and survival. It is also critically involved in tumorigenesis and cancer progression. A key enzyme in the activation of Notch signaling is the gamma-secretase protein complex and therefore, gamma-secretase inhibitors (GSIs)originally developed for Alzheimer's disease-are now being evaluated in clinical trials for human malignancies. It is also clear that Notch plays an important role in angiogenesis driven by Vascular Endothelial Growth Factor A (VEGF-A)-a process instrumental for tumor growth and metastasis. The effect of GSIs on tumor vasculature has not been conclusively determined. Here we report that Compound X (CX), a GSI previously reported to potently inhibit Notch signaling in vitro and in vivo, promotes angiogenic sprouting in vitro and during developmental angiogenesis in mice. Furthermore, CX treatment suppresses tumor growth in a mouse model of renal carcinoma, leads to the formation of abnormal vessels and an increased tumor vascular density. Using a rabbit model of VEGF-A-driven angiogenesis in skeletal muscle, we demonstrate that CX treatment promotes abnormal blood vessel growth characterized by vessel occlusion, disrupted blood flow, and increased vascular leakage. Based on these findings, we propose a model for how GSIs and other Notch inhibitors disrupt tumor blood vessel perfusion, which might be useful for understanding this new class of anti-cancer agents.
|
|
| 9. |
- Kalén, Mattias
(författare)
-
On angiogenesis modulation
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- During evolution, the transition from unicellular to multicellular organisms required the origin of a transport system capable of interconnecting specialized cells throughout the body of the organism. In higher animals, this route of transportation is the cardiovascular system, which allows gas exchange, and transport of immune cells, hormones, macromolecules, nutrients and waste products. Due to its central role, supporting other organs and tissues, the cardiovascular system forms early during the embryonic development and is the first functional organ of the body. The construction of a vascular system can seem to be trivial (a circuit of patent tubes of various diameters, how complicated can it be?), but it is not. First, the system contains many different cell types that interact with one another. Endothelial cells constitute the actual tube in contact with the blood. Mural cells, either vascular smooth muscle cells around larger vessels, or pericytes in the case of the capillaries, “wrap” the endothelium and exert vasoactive control, provide it with structural support, and instructive molecular cues. Second, many cellular processes including oxygen sensing, proliferation, differentiation, apoptosis, and adhesion are at work when a vascular system is formed, all requiring tight regulation and coordination. Third, different vascular beds have different properties, which need to be established and regulated via cell signaling. For example, compare the difference in permeability of the kidney endothelium with that of the blood- brain barrier. The phenomenon of blood vessel formation from pre-existing ones – angiogenesis – has been known for at least 100 years, and has been implicated in the pathology of many diseases, which in turn has sparked intensive research in the field in recent years. However, despite a tremendous effort to map and master this biological process, it is evident – given the somewhat meager results in the clinic – that more knowledge on how blood vessels are formed is required before effective drugs, inhibiting or stimulating angiogenesis, can be generated. For example, the identities of all genes involved are not known and more important, the principles of angiogenesis, according to which these genes effectuate their respective roles, are still very much in the dark. Herein, I describe work aimed at identifying genes and chemical compounds previously not implicated in angiogenesis, as well as at characterizing the role of angiogenesis modulating genes. Included is: i) how the regulator of G-protein coupled signaling RGS5 was identified as a novel marker for pericytes; ii) how the role of Notch signaling in angiogenesis was characterized, and shown to regulate the number of endothelial tip cells, in turn affecting the density of the resulting vascular plexus; iii) how sixteen genes and twenty-eight compounds modulating angiogenesis were identified, and a role for the serine/threonine (S/T) phosphatases PPP1CA, PPP1CC, and PPP4C was uncovered using – for the first time in vertebrates – a combination of reverse and chemical genetics; and finally iv) how the drug Perhexiline maleate for the treatment of angina pectoris, was identified as an anti-angiogenic compound, using a functional cell-based chemical screen.
|
|
| 10. |
- Scheidl, Stefan Johannes, 1972, et al.
(författare)
-
mRNA expression profiling of laser microbeam microdissected cells from slender embryonic structures.
- 2002
-
Ingår i: The American journal of pathology. - 0002-9440. ; 160:3, s. 801-13
-
Tidskriftsartikel (refereegranskat)abstract
- Microarray hybridization has rapidly evolved as an important tool for genomic studies and studies of gene regulation at the transcriptome level. Expression profiles from homogenous samples such as yeast and mammalian cell cultures are currently extending our understanding of biology, whereas analyses of multicellular organisms are more difficult because of tissue complexity. The combination of laser microdissection, RNA amplification, and microarray hybridization has the potential to provide expression profiles from selected populations of cells in vivo. In this article, we present and evaluate an experimental procedure for global gene expression analysis of slender embryonic structures using laser microbeam microdissection and laser pressure catapulting. As a proof of principle, expression profiles from 1000 cells in the mouse embryonic (E9.5) dorsal aorta were generated and compared with profiles for captured mesenchymal cells located one cell diameter further away from the aortic lumen. A number of genes were overexpressed in the aorta, including 11 previously known markers for blood vessels. Among the blood vessel markers were endoglin, tie-2, PDGFB, and integrin-beta1, that are important regulators of blood vessel formation. This demonstrates that microarray analysis of laser microbeam micro-dissected cells is sufficiently sensitive for identifying genes with regulative functions.
|
|
| 11. |
- Wallgard, Elisabet, et al.
(författare)
-
Paladin (X99384) is expressed in the vasculature and shifts from endothelial to vascular smooth muscle cells during mouse development
- 2012
-
Ingår i: Developmental Dynamics. - : Wiley. - 1058-8388 .- 1097-0177. ; 241:4, s. 770-786
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Angiogenesis is implicated in many pathological conditions. The role of the proteins involved remains largely unknown, and few vascular-specific drug targets have been discovered. Previously, in a screen for angiogenesis regulators, we identified Paladin (mouse: X99384, human: KIAA1274), a protein containing predicted S/T/Y phosphatase domains.Results: We present a mouse knockout allele for Paladin with a beta-galactosidase reporter, which in combination with Paladin antibodies demonstrate that Paladin is expressed in the vasculature. During mouse embryogenesis, Paladin is primarily expressed in capillary and venous endothelial cells. In adult mice Paladin is predominantly expressed in arterial pericytes and vascular smooth muscle cells. Paladin also displays vascular-restricted expression in human brain, astrocytomas, and glioblastomas.Conclusions: Paladin, a novel putative phosphatase, displays a dynamic expression pattern in the vasculature. During embryonic stages it is broadly expressed in endothelial cells, while in the adult it is selectively expressed in arterial smooth muscle cells.
|
|
