| 1. |
- Miloudi, Khalil, et al.
(författare)
-
NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy
- 2019
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 116:10, s. 4538-4547
-
Tidskriftsartikel (refereegranskat)abstract
- Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from beta-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.
|
|
| 2. |
- Smith, Ross, 1983-
(författare)
-
Biological consequences of endothelial cell signaling
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Endothelial cells make up the inner lining of blood and lymphatic vessels, where they participate in functions vital to survival of the tissue; endothelial cells maintain vessel integrity, dynamically respond to the changing metabolic needs of tissues, and participate in many tissue-specific functions. Endothelial cells sense environmental cues which initiate signal transduction pathways that regulate behavior. Endothelial cell dysfunction is a feature of many diseases, such as cancer, atherosclerosis, and retinopathies and therefore knowledge of endothelial signal transduction pathways is important for designing therapies to treat these diseases.The receptor tyrosine kinase VEGFR2 is a master regulator of endothelial cell biology, regulating survival, growth, migration, angiogenesis and vessel permeability. VEGF stimulation of VEGFR2 results in phosphorylation of tyrosine residues in the receptor’s intracellular domain. The phosphorylation of Y949, Y1173, and Y1212 is known to initiate complex signaling pathways in endothelial cells, but it is still unclear how each individual phosphosite contributes to overall endothelial regulation. The scaffold protein palmdelphin has been found to be highly expressed in endothelial cells, though its role in endothelial biology is still unclear.In this thesis I present investigations of endothelial cell signaling pathways. In Paper I, we identify VEGFR2 pY1212 binding partners and use a mouse model to reveal the effect of abrogated Y1212 signaling in vivo. In Paper II, we investigate endothelial palmdelphin and establish that loss of palmdelphin in vitro and in vivo results in morphological changes for endothelial cells. Additionally, loss of palmdelphin leads to a misalignment of endothelial nuclei in response to flow, implicating palmdelpin in a mechanotransduction pathway. In Paper III, we use mouse models of proliferative retinopathy to demonstrate that loss of VEGFR2 Y949 signaling leads to a reduction or delay in neovascularization and a decrease in vessel leakage from pathological lesions.In summary, the investigation of endothelial cell signal transduction pathways can help us understand and unravel the complexities of vascular biology. Designing therapies which affect only a specific signaling axis has the potential to reduce side effects and optimize treatment.
|
|
| 3. |
- Stahl, Andreas, et al.
(författare)
-
Lipid metabolites in the pathogenesis and treatment of neovascular eye disease.
- 2011
-
Ingår i: The British journal of ophthalmology. - : BMJ. - 0007-1161. ; 95:11, s. 1496-1501
-
Tidskriftsartikel (refereegranskat)abstract
- Lipids and lipid metabolites have long been known to play biological roles that go beyond energy storage and membrane structure. In age-related macular degeneration and diabetes, for example, dysregulation of lipid metabolism is closely associated with disease onset and progression. At the same time, some lipids and their metabolites can exert beneficial effects in the same disorders. This review summarises our current knowledge of the contributions of lipids to both the pathogenesis and treatment of neovascular eye disease. The clinical entities covered are exudative age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity, with a special emphasis on the potential therapeutic effects of ω3- (also known as n-3) polyunsaturated fatty acids.
|
|
| 4. |
- Stahl, Andreas, et al.
(författare)
-
Postnatal weight gain modifies severity and functional outcome of oxygen-induced proliferative retinopathy
- 2010
-
Ingår i: The American journal of pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 177:6, s. 2715-23
-
Tidskriftsartikel (refereegranskat)abstract
- In clinical studies, postnatal weight gain is strongly associated with retinopathy of prematurity (ROP). However, animal studies are needed to investigate the pathophysiological mechanisms of how postnatal weight gain affects the severity of ROP. In the present study, we identify nutritional supply as one potent parameter that affects the extent of retinopathy in mice with identical birth weights and the same genetic background. Wild-type pups with poor postnatal nutrition and poor weight gain (PWG) exhibit a remarkably prolonged phase of retinopathy compared to medium weight gain or extensive weight gain pups. A high (r(2) = 0.83) parabolic association between postnatal weight gain and oxygen-induced retinopathy severity is observed, as is a significantly prolonged phase of proliferative retinopathy in PWG pups (20 days) compared with extensive weight gain pups (6 days). The extended retinopathy is concomitant with prolonged overexpression of retinal vascular endothelial growth factor in PWG pups. Importantly, PWG pups show low serum levels of nonfasting glucose, insulin, and insulin-like growth factor-1 as well as high levels of ghrelin in the early postoxygen-induced retinopathy phase, a combination indicative of poor metabolic supply. These differences translate into visual deficits in adult PWG mice, as demonstrated by impaired bipolar and proximal neuronal function. Together, these results provide evidence for a pathophysiological correlation between poor postnatal nutritional supply, slow weight gain, prolonged retinal vascular endothelial growth factor overexpression, protracted retinopathy, and reduced final visual outcome.
|
|
| 5. |
- Stahl, Andreas, et al.
(författare)
-
The mouse retina as an angiogenesis model.
- 2010
-
Ingår i: Investigative ophthalmology & visual science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 51:6, s. 2813-26
-
Tidskriftsartikel (refereegranskat)abstract
- The mouse retina has been used extensively over the past decades to study both physiologic and pathologic angiogenesis. Over time, various mouse retina models have evolved into well-characterized and robust tools for in vivo angiogenesis research. This article is a review of the angiogenic development of the mouse retina and a discussion of some of the most widely used vascular disease models. From the multitude of studies performed in the mouse retina, a selection of representative works is discussed in more detail regarding their role in advancing the understanding of both the ocular and general mechanisms of angiogenesis.
|
|
