Role of NO-sensitive guanylyl cyclase during liver fibrosis in mice

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Our lab focuses on the physiological and pathophysiological role of the NO receptor, NO-sensitive guanylyl cyclase (NO-GC). We have generated mice with global or cell-specific deficiency for NO-GC. Recent work has been focusing on the effect of NO on gut peristalsis, blood pressure regulation and angiogenesis. With this project we would like to investigate the influence of NO/cGMP signaling on liver fibrosis.Preliminary data show NO-GC to be expressed in hepatic stellate cells (HSC), the pericytes of the liver. HSC have been shown to participate in wound healing and fibrotic response after liver injury. Our preliminary data indicate the existence of HSC and 'true' pericytes in the liver lobule. Both cell types express NO-GC but they differ in their lobular distribution. In the first subproject, we will carefully describe NO-GC expression (including NO-GC subunits) in different cells of the liver. In the second part, we will use primary cultures of HSC and pericytes to investigate the mechanistic contribution of NO-GC in vitro. We will proceed in describing the participation of NO-GC in the fibrotic response in vivo. We will employ the carbon tetrachloride model for liver fibrosis in the mouse that mimics several aspects of the human disease. In order to evaluate the role of HSC and pericytes, we will use our different Cre/KO strains (Lrat-Cre; SMMHC-CreERT2). Methods used include immunohistochemistry using a confocal microscope, lineage tracing with reporter strains, qPCR, collagen assays or in situ hybridization. In addition, we plan to investigate the antifibrotic effects of a NO-GC stimulator. With this translational approach, we will fathom the potential therapeutic use of NO-GC stimulation.In summary, we expect to obtain a detailed view on how NO-GC in HSC and pericytes participates in liver fibrosis. By comparing two different models of liver fibrosis in vitro and in vivo we not only expect mechanistic details but we also will gather valuable information on the therapeutic use of the NO/cGMP cascade for fibrotic diseases.