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The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure
Author(s) -
Fargali Samira,
Garcia Angelo L.,
Sadahiro Masato,
Jiang Cheng,
Janssen William G.,
Lin WeiJye,
Cogliani Valeria,
Elste Alice,
Mortillo Steven,
Cero Cheryl,
Veitenheimer Britta,
Graiani Gallia,
Pasinetti Giulio M.,
Mahata Sushil K.,
Osborn John W.,
Huntley George W.,
Phillips Greg R.,
Benson Deanna L.,
Bartolomucci Alessandro,
Salton Stephen R.
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-239509
Subject(s) - endocrinology , medicine , adrenal medulla , catecholamine , chromogranin a , epinephrine , adrenal gland , blood pressure , knockout mouse , biology , chemistry , receptor , immunohistochemistry
Secretion of proteins and neurotransmitters from large dense core vesicles (LDCVs) is a highly regulated process. Adrenal LDCV formation involves the granin proteins chromogranin A (CgA) and chromogranin B (CgB); CgA‐ and CgB‐derived peptides regulate catecholamine levels and blood pressure. We investigated function of the granin VGF (nonacronymic) in LDCV formation and the regulation of catecholamine levels and blood pressure. Expression of exogenous VGF in non‐endocrine NIH 3T3 fibroblasts resulted in the formation of LDCV‐like structures and depolarization‐induced VGF secretion. Analysis of germline VGF‐knockout mouse adrenal medulla revealed decreased LDCV size in noradrenergic chromaffin cells, increased adrenal norepinephrine and epinephrine content and circulating plasma epinephrine, and decreased adrenal CgB. These neurochemical changes in VGF‐knockout mice were associated with hypertension. Germline knock‐in of human VGF 1–615 into the mouse Vgf locus rescued the hypertensive knockout phenotype, while knock‐in of a truncated human VGF 1–524 that lacks several C‐terminal peptides, including TLQP‐21, resulted in a small but significant increase in systolic blood pressure compared to hVGF 1–615 mice. Finally, acute and chronic administration of the VGF‐derived peptide TLQP‐21 to rodents decreased blood pressure. Our studies establish a role for VGF in adrenal LDCV formation and the regulation of catecholamine levels and blood pressure.—Fargali, S., Garcia, A. L., Sadahiro, M., Jiang, C., Janssen, W. G., Lin, W.‐J., Cogliani, V., Elste, A., Mortillo, S., Cero, C., Veitenheimer, B., Graiani, G., Pasinetti, G. M., Mahata, S. K., Osborn, J. W., Huntley, G. W., Phillips, G. R., Benson, D. L., Bartolomucci, A.,Salton, S. R. The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure. FASEB J . 28, 2120–2133 (2014). www.fasebj.org