Blood Pressure Control by a Secreted FGFBP1 (Fibroblast Growth Factor–Binding Protein)

Fibroblast growth factors (FGFs) participate in organ development and tissue maintenance, as well as the control of vascular function. The paracrine-acting FGFs are stored in the extracellular matrix, and their release is controlled by a secreted FGF-binding protein (FGF-BP, FGFBP1, and BP1) that mo...

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Published in:	Hypertension (Dallas, Tex. 1979) Vol. 71; no. 1; pp. 160 - 167
Main Authors:	Tassi, Elena, Lai, En Yin, Li, Lingli, Solis, Glenn, Chen, Yifan, Kietzman, William E, Ray, Patricio E, Riegel, Anna T, Welch, William J, Wilcox, Christopher S, Wellstein, Anton
Format:	Journal Article
Language:	English
Published:	United States American Heart Association, Inc 01-01-2018
Subjects:	Angiotensin II Type 1 Receptor Blockers - pharmacology Animals Benzimidazoles - pharmacology Biphenyl Compounds Blood Pressure - drug effects Blood Pressure - physiology Carrier Proteins - genetics Carrier Proteins - metabolism Cyclic N-Oxides - pharmacology Disease Models, Animal Fibroblast Growth Factors - metabolism Humans Hypertension - drug therapy Hypertension - genetics Hypertension - metabolism Intercellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins Mice Mice, Transgenic Mitogen-Activated Protein Kinases - metabolism Protein Synthesis Inhibitors - pharmacology Signal Transduction - drug effects Spin Labels Tetrazoles - pharmacology Vasoconstriction - drug effects Vasoconstriction - physiology vascular resistance blood pressure fibroblast growth factor angiotensin II reactive oxygen species
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Summary:	Fibroblast growth factors (FGFs) participate in organ development and tissue maintenance, as well as the control of vascular function. The paracrine-acting FGFs are stored in the extracellular matrix, and their release is controlled by a secreted FGF-binding protein (FGF-BP, FGFBP1, and BP1) that modulates FGF receptor signaling. A genetic polymorphism in the human FGFBP1 gene was associated with higher gene expression and an increased risk of familial hypertension. Here, we report on the effects of inducible BP1 expression in a transgenic mouse model. Induction of BP1 expression in adult animals leads to a sustained rise in mean arterial pressure by >30 mm Hg. The hypertensive effect of BP1 expression is prevented by candesartan, an angiotensin II (AngII) receptor antagonist, or by tempol, an inhibitor of reactive oxygen species. In vivo, BP1 expression sensitizes peripheral resistance vessels to AngII constriction by 20-fold but does not alter adrenergic vasoconstriction. FGF receptor kinase inhibition reverses the sensitization to AngII. Also, constriction of isolated renal afferent arterioles by AngII is enhanced after BP1 expression and blocked by FGF receptor kinase inhibition. Furthermore, AngII-mediated constriction of renal afferent arterioles is abolished in FGF2 mice but can be restored by add-back of FGF2 plus BP1 proteins. In contrast to AngII, adrenergic constriction is not affected in the FGF2 model. Proteomics and gene expression analysis of kidney tissues after BP1 induction show that MAPK (mitogen-activated protein kinase) signaling via MKK4 (MAPK kinase 4), p38, and JNK (c-Jun N-terminal kinase) integrates the crosstalk of the FGF receptor and AngII pathways and thus impact vascular tone and blood pressure.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0194-911X 1524-4563
DOI:	10.1161/HYPERTENSIONAHA.117.10268