Protein Tyrosine Phosphatase-1B and vascular signal transduction in obesity

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Overexpression of counterregulatory mediators, such as protein tyrosine phosphatase 1B (PTP1B), has been implicated in disorders of central nervous control mechanisms of food intake and energy balance and the development of leptin and insulin resistance in obesity. Substrates of PTP1B include receptor tyrosine kinases, but also structural proteins such as caveolin-1, proteases such as calpain, or integrin modulators such as Src kinase and cortactin, i.e. factors with critical relevance for vascular homeostasis. However, the importance of PTP1B for the signal transduction of vascular cells and the vascular complications of obesity are incompletely understood. Our own preliminary work shows that the lack of PTP1B in endothelial cells increases the expression of caveolin-1 and the formation of reactive oxygen species and accelerates the development of senescence, while mice with genetic deletion of PTP1B in smooth muscle cells develop an increased perivascular fibrosis after vascular wall injury. Moreover, PTP1B has been shown to interfere with the tropomyosin receptor kinase (Trk)-mediated signal transduction of neurotrophins. Neurotrophins and their receptors are expressed in adipose tissue and vascular cells, among others, and first data suggest functions in the control of vascular tone, smooth muscle cell proliferation and extracellular matrix production. In the proposed project, the importance of PTP1B for disorders of vascular function will be examined and the underlying mechanisms elucidated using primary cells, animal models and patient biomaterial. On the basis of (own) preparatory work, the significance of PTP1B for the development of aging processes in the vascular endothelium will be clarified and the involved mediators will be identified. In addition, it will be investigated whether and how oxidative stress and senescence contribute to perivascular fibrosis in the absence of PTP1B in myofibroblasts and perivascular progenitor cells. In addition, we will determine how absence of the neurotrophin receptor TrkB in smooth muscle cells affects neointima formation and how obesity or PTP1B influence the expression of neurotrophic mediators and their receptors in the vessel wall and perivascular adipose tissue.