Research

The primary goal of our research is to understand how signaling pathways in the endothelium affect vascular development, the flux of nutrients and hormones to parenchymal cells in an organ-specific manner and the interactions with tumor cells. We want to pave the way to translate these basic findings into clinical relevance.

Vascular Signaling

Our main focus is the Delta-Notch pathway, which transmits signals between adjacent cells. Notch signaling is a major regulator of angiogenesis. We have identified several modifiers and novel target genes of this signaling cascade. These genes are critical to control blood vessel formation during development and in solid tumors (Adam et al., Circ Res. 2013;  Berger et al., Cardiovasc Res. 2015; Wöltje et al., PlosONE. 2015; Klose et al., under review; Tetzlaff et al., under review).

We have previously identified disturbed Notch signaling as a fundamental cue during the pathogenesis of certain neurovascular malformations (cerebral cavernous malformations) which increase the risk for stroke (Wüstehube et al., PNAS. 2010; Brütsch et al., Circ Res. 2010). In recent studies, we could show that Notch signaling controls proper formation of the blood vessel wall and that this is impaired in cerebral cavernous malformations (Schultz et al., Stroke, 2015).

Currently, we are addressing how Notch and Semaphorin-3C act on mature and immature blood vessels and how this can be used to interfere with pathological angiogenesis (Yang et al., EMBO Mol Med, 2015). We analyze how novel Notch modifying proteins control neurovascular developement and can be used to target tumor angiogenesis (Tetzlaff et al., under review; Feldner et al., EMBO Mol Med, 2017).

The Endothelium as a Central Regulator of Metabolism

The endothelium is in direct contact with the blood and transports nutrients and hormones to almost all tissues. Therefore, an intact endothelium should control all major aspects of metabolism. We are analyzing this by inducing endothelial-specific defects in mouse models as well as in cellular systems. Our data showed that the endothelium responds to altered nutrient concentration (e.g. different diets, diabetes mellitus models) by changing the gene expression profile. This alters, for example, the expression levels of certain endothelial transporters for fatty acids, glucose and insulin. Subsequently, genetic alterations in endothelial cells exert profound effects for nutrient and hormone supply to parenchymal cells. This dramaticall changes organ function (Jabs et al, in revision; Jabs et al, submitted). Future work will address how such changes alter metabolism in the tumor microenvironment and how this can be used to define novel therapeutic strategies.

Control of immune cell recruitment and immune cell polarization by the endothelium (Project Leader: Dr. Juan Rodriguez-Vita)

Chronic inflammation is a key driver of tumor progression. Although immune cells are initially recruited to fight the tumor cells, often a rapid switch occurs that changes the behavior of immune cells to adopt a tumor-promoting phenotype. The understanding of how immune cells are recruited and how these cells are polarized is a key issue in tumor biology. We are just starting to understand how the endothelium is actively involved in this. Our previous studies have for instance shown that hyperactive Notch signaling in the tumor endothelium promotes recruitment of myeloid-derived suppressor cells (Wieland, Rodriguez-Vita et al., Cancer Cell, 2017). We are currently analysing how factors, secreted by tumor cells and tumor endothelial cells modify immune cell recruitment and immune cell polarization.

Fibrosis as a target for vascular normalization (Project Leader: Dr. Juan Rodriguez-Vita)

Blood vessels are in intimate contact with fibroblasts within many organs and there is increasing evidence that fibroblast-derived factors control angiogenesis and blood vessel functions. However, also blood vessel-secreted factors could control fibroblast functions. Fibroblasts secrete many proteins of the extracellular matrix. Upon organ damage, fibroblast can trans-differentiate into myofibroblasts, which promote the development of organ fibrosis. Myofibroblasts modify the extracellular matrix, and this changes blood flow and organ function. Our research focuses on the mechanisms by which Semaphorin class-3 proteins secreted from blood vessels control controls fibroblast behavior. We analyze how Semaphorin proteins alter the response of fibroblasts towards pro-fibrotic factors, how this influences the composition of the extracellular matrix, blood vessel morphology and function, and the progression of organ fibrosis.

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