The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure

Samira Fargali, Angelo L. Garcia, Masato Sadahiro, Cheng Jiang, William G. Janssen, Wei Jye Lin, Valeria Cogliani, Alice Elste, Steven Mortillo, Cheryl Cero, Britta Veitenheimer, Gallia Graiani, Giulio M. Pasinetti, Sushil K. Mahata, John W. Osborn, George W. Huntley, Greg R. Phillips, Deanna L. Benson, Alessandro Bartolomucci, Stephen R. Salton

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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 nonendocrine 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 VGF1-615 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 hVGF1-615 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.

Original languageEnglish (US)
Pages (from-to)2120-2133
Number of pages14
JournalFASEB Journal
Volume28
Issue number5
DOIs
StatePublished - May 2014

Keywords

  • Adrenal
  • CG
  • Chromaffin granule
  • LDCV
  • Large dense core vesicle
  • Norepinephrine

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