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von Willebrand factor-mediated monocyte extravasation and macrophage polarisation in arteriogenesis

Description

In the initiation and progression of most vascular remodelling processes there exists a link between haemostasis and innate immunity but the underlying intercellular crosstalk still remains elusive. In this context, we have established that depending on the hemodynamic situation endothelial cells tightly control the amount and functionality of CD40 present on their surface.1,2 Moreover, CD40 ligation of both cultured and native endothelial cells promotes their release of von Willebrand factor (vWF)3 which is primarily deposited as ultra-large vWF multimers on their surface in the presence of flow. Platelets rapidly adhere to these multimers, turn P-selectin positive and recruit circulating monocytes even at very high flow. In addition, CD154 stimulation of endothelial cells evokes expression of the ligand itself on their surface.4

 

Hypothesis: As shown for pulmonary arterioles, arteriolar leukocyte extravasation also occurs in arteriogenesis in vivo. This is brought about by vWF-platelet dependent leukocyte recruitment to the endothelial cell contacts. Upon transmigration endothelial cell CD154-monocyte CD40 co-stimulation promotes monocyte to pro-inflammatory macrophage differentiation while the endothelial cells conversely are stimulated to change their matrix protein synthesis and production of cytokines to attract perivascular cells thereby facilitating remodelling.

 

Objectives: In close collaboration with partner LMU a multiphoton-based life cell imaging method will be set up to visualize the vWF-platelet mediated intercellular crosstalk in arterioles of the mouse ear pinna. The ESR will then adapt this method to the corresponding arteriogenesis model5 of partner UKH, first of all comparing conditional endothelial cell-specific CD40 knockdown mice with wild type animals.

 

Training: The ESR will be jointly supervised by partners LMU and UKH. To learn the multiphoton live cell imaging method, he/she will spend 8 months with partner LMU under the co-supervision by Steffen Dietzel. In addition, he/she will train 1 month with partner DMT to adapt the imaging method to isolated perfused mouse blood vessels.

1 Korff T. Circulation 2007; 116:2288-2297. 2 Wagner AH. Blood 2011; 118:3734-3742. 3 Möller K. Blood 2012; submitted. 4 Wagner AH. ATVB 2004; 24:715-720. 5 Demicheva E . Circ Res 2008 ; 103:477-484.

Publications

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Ph.D student / post-doc

Sibgha Tahir

Principal Investigator

Prof. Markus Hecker