Importance of the EGF receptor and the smooth muscle-endothelial interaction for the effects of obesity-associated milieu changes on vascular cells.

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The increasing frequency of obesity contributes significantly to the prevalence of cardiovascular diseases. Obesity-associated milieu changes (OAMC) can directly affect vascular wall homeostasis. Work from the previous project period shows the important role of EGF receptor (EGFR), as a signal integrator in vascular information processing. Our data show that the vascular muscle (VSMC)-EGFR contributes to high-fat diet (HFD)-induced vascular and renal changes. The potentiation of the EGFR/ErbB2-ROCK-MRTF-SRF signaling axis and mitochondrial dysfunction play an important role here. In addition, there is a VSMC-EGFR-dependent interaction between VSMC and endothelial cells (EC). The EC-EGFR, on the other hand, is of lesser and partly contrary importance for vascular function per se, as well as for HFD-induced damage. The observed EGFR-mediated expression of TGFβ and CTGF in primary VSMC represents a possible mechanism of interaction. In preliminary experiments we were able to show that the effect of EGF on the transcriptome of primary VSMC (wildtype but not EGFR-KO) is enhanced by glucose and that there is, among other things, a synergism with regard to the expression of osteopontin, also a candidate for the VSMC-EC interaction.Objective: Analyzing the importance of EGFR for the effects of OAMC on primary VSMC and EC and of cellular interaction. The components of OAMC to be examined include metabolic stress (glucose, free fatty acids) and humoral stress (angiotensin II, norepinephrine).Action need: Our main working hypotheses state that the VSMC-EGFR is necessary for pathological vascular changes in VSMC and EC. Here, a VSMC-EGFR-dependent interaction between VSMC and EC takes place. Resulting alterations of EC can also include a weakening of positive effects of EC-EGFR and detrimental feedback of affected EC on VSMC. The interaction hypothesis, the involvement of EGFR and its relevance for human vascular cells must now be examined and the mechanisms of information transfer identified.Action concept: We will carry out comparative experiments with murine and human primary VSMC and EC in mono- and co-culture. The mouse models allow the role of EGFR to be investigated in a cell-specific manner by comparing cells from EGFR-KO animals and WT animals in coculture. Cells of transgenic mouse models have contributed significantly to the mechanistic understanding of pathophysiological processes. However, the transfer to human cells was often not possible, so that the use of ex vivo primary human cell culture systems is necessary. EGFR inhibitors are then used in the human model. The following work packages for testing the corresponding hypotheses are planned: 1. proliferation, senescence, cell death; 2. energy homeostasis; 3. extracellular matrix; 4. inflammation; 5&6. inter- and intracellular signal transduction. With regard to information transfer, intercellular communication is exam-ined by means of media analysis and intervention experiments.