Impact of soluble Flt-1 on endothelial cell activation and its implications in leukocyte adhesion and microvascular dysfunction in ischemia-reperfusion injury
Final Report Abstract
The vascular endothelium represents a permeable barrier capable of recognizing various signals. Disturbance of endothelial homeostasis increases vascular permeability, inflammation, and cellular transdifferentiation. Activation of endothelial cells and inflammation result in the adhesion and entry of leukocytes in the vessel wall and in disturbance of microcirculation, critical processes involved in kidney damage, e.g., in the setting of renal ischemia-reperfusion (IR) injury. A possible explanation for the lack of vascular repair in several renal diseases is that renal injury results in a shift of expressed factors in favor of anti-angiogenesis vs. angiogenesis/vascular stabilization. By neutralizing the vascular endothelial growth factor (VEGF), a crucial cytokine for angiogenesis and endothelial cell maintenance, elevated sFlt-1 levels contribute to the impairment of endothelial repair, chronically compromising endothelial function and the microvasculature. However, if the role of sFlt-1 in causing endothelial dysfunction is well characterized, its role in endothelial inflammation is poorly explored. Even though we could not find a direct impact of sFlt-1 in leukocyte infiltration in the mouse model of renal ischemia-reperfusion, we described in this project two additional mechanisms by which sFlt-1 may affect endothelial homeostasis: 1) the collapse of the endothelial glycocalyx and 2) the stiffening of the endothelial cortex. Interestingly, the damage of the eGC has been suggested to be the leading cause of endothelial dysfunction in various inflammatory and kidney diseases. By decreasing eGC height and increasing its stiffness, sFlt-1 facilitates the adherence of monocytes to the endothelium and favors inflammation. On the other hand, changes in the endothelial cortical stiffness provide a comprehensive analysis of the status of the endothelial cell structure and function under high sFlt-1 conditions. Taking into consideration that sFlt-1 is increased in many diseases, such as preeclampsia, chronic kidney disease, and renal ischemia-reperfusion, but also heart failure and viral infections like COVID-19, our findings may help to explain many of the varied adverse outcomes related to sFlt-1 that cannot be exclusively ascribed to the inhibition angiogenesis.
Publications
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Bedeutung des solublen VEGF-Rezeptors-1 für die gestörte renale Mikrostrombahn im Tiermodell der akuten Nierenerkrankung (Ischämie- Reperfusions-Modell der Maus).
Wewers T.
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Circulating Soluble Fms-like Tyrosine Kinase in Renal Diseases Other than Preeclampsia. Journal of the American Society of Nephrology, 32(8), 1853-1863.
Wewers, Theresa M.; Schulz, Annika; Nolte, Ingo; Pavenstädt, Hermann; Brand, Marcus & Di Marco Giovana, S.
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Lösliche fmslike tyrosine kinase-1 (sFlt-1) verursacht Schäden an der endothelialen Glycocalyx. Poster 146, Kongress für Nephrologie 2021 – 13. Jahrestagung der Deutschen Gesellschaft für Nephrologie.
Schulz A., Hesse B., Beul K., Lukasz A.H., Di Marco G.S. & Brand M.
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Damage of the endothelial glycocalyx and cortical stiffening - two new mechanisms of action of soluble Fms-like tyrosine kinase (sFlt-1) contributing to endothelial dysfunction beyond angiogenesis.
Schulz A.
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The Soluble Fms-like Tyrosine Kinase-1 Contributes to Structural and Functional Changes in Endothelial Cells in Chronic Kidney Disease. International Journal of Molecular Sciences, 23(24), 16059.
Schulz, Annika; Drost, Carolin Christina; Hesse, Bettina; Beul, Katrin; Brand, Marcus & Di, Marco Giovana Seno
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The Endothelial Glycocalyx as a Target of Excess Soluble Fms-like Tyrosine Kinase-1. International Journal of Molecular Sciences, 24(6), 5380.
Schulz, Annika; Drost, Carolin C.; Hesse, Bettina; Beul, Katrin; Boeckel, Göran R.; Lukasz, Alexander; Pavenstädt, Hermann; Brand, Marcus & Di Marco Giovana, S.
