Oxidative Stress, Hypertension and an FGF-binding Protein

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Fibroblast growth factors (FGF-1 or -2) are present at significant concentrations in most normal tissues in the adult. However, these FGFs are immobilized in an inactive state on the extracellular matrix and it is only poorly understood how they are solubilized and activated to reach their extracellular receptors. One mechanism through which FGFs can be mobilized is by binding to secreted binding proteins (BPs) and we showed that BP1 can enhance the activity of locally stored, immobilized FGFs. BP1 expression is controlled by stress pathways in cultured cells and found upregulated after wounding, toxic or infectious injury of the skin or kidneys. BP1 expression in mice carrying an inducible BP1 transgene caused a significant rise in mean arterial blood pressure (MAP) by +30 mm Hg within two days of transgene induction and analysis of vascular contractility showed a sensitization to angiotensin II. The rise of MAP after BP1 transgene expression was inhibited by systemic administration of the superoxide dismutase mimetic Tempol suggesting an essential role of oxidative stress. We hypothesize that BP1/FGF signaling modulates the sensitivity of blood vessels towards contractile signaling and propose to study this under the following aims: Aim 1. To evaluate the contribution of FGF-2 or other FGFs to the BP1-induced hypertensive effect. We will study blood pressure, vessel contractility and renal tubular function in FGF-2(-/-) mice that are crossed with mice carrying an inducible BP1 transgene. Systemic administration of BP1 and FGF-2 will complement this. Aim 2. To study the contribution of kidney expression of BP1 to blood pressure regulation, vessel contractility and renal tubular function we will use mice harboring a HoxB7-controlled, tetracycline inducible BP1 transgene. To evaluate the role of endogenous BP1 to oxidative stress-regulated blood pressure, we will generate mice that are null for BP1 expression. Aim 3. To study the intracellular cross-talk between BP1 / FGF signaling and G-protein coupled receptor pathways we will monitor signal transduction and phenotypic effects in preglomular smooth muscle cells from experimental animals. Biochemical signaling via known integrators of the pathways (i.e. MAPKs) and proliferation/cell survival and superoxide generation will be used as read-outs. Mass spectrometry to identify new signaling proteins in the cross-talk will complement this.