Oxidative Stress, Hypertension and an FGF-binding Protein

Georgetown University, Washington DC

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Abstract

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