The primary goal of our research is to understand how signaling pathways in the endothelium affect vascular development, the flux of nutrients to muscle cells 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., in preparation).

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 Semaphorin-3C acts on mature and immature blood vessels and how this can be used to interfere with pathological angiogenesis in the retina (Yang et al., EMBO Mol Med, 2015) and other diseases (Rodriguez-Vita et al., in preparation).

Interactions between Endothelial Cells and Tumor Cells

Tumor cells are in close contact with blood vessels. Therefore, endothelial cells do not only form new blood vessels to nourish the growing tumor mass but  also provide soluble factors and surface molecules that orchestrate tumor progression and metastasis. This has been described as angiocrine signaling.

We study how the endothelium actively controls the entry and the exit of tumor cells and certain immune cells into/from blood vessels. Our research revealed a novel crosstalk between endothelial cells, neutrophils and tumor cells of ultimate importance for several steps of the metastasis cascade (Wieland, Rodriguez-Vita et al., Cancer Cell 2017). Currently, we are examining if blockade of this signaling cascade could be employed to inhibit metastatic spreading of tumor cells.

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 upon consumption of different diets 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 supply of heart muscle and heart function (Jabs et al, in revision). Moreover, endothelial cell functions are also critical for insulin sensitivity and are thereby implicated in the pathogenesis of diabetes (Jabs et al., in preparation). Future work will address how this changes metabolism in the tumor microenvironment.

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