RT Journal Article
SR Electronic
T1 Mast Cell Degranulation Increases Mouse Mast Cell Protease 4–Dependent Vasopressor Responses to Big Endothelin-1 But Not Angiotensin I
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 213
OP 221
DO 10.1124/jpet.120.000325
VO 376
IS 2
A1 Laurence Vincent
A1 Catherine Lapointe
A1 Modou Lo
A1 Hugo Gagnon
A1 Gunnar Pejler
A1 Shinji Takai
A1 Robert Day
A1 Pedro D’Orléans-Juste
YR 2021
UL http://jpet.aspetjournals.org/content/376/2/213.abstract
AB Mouse mast cell protease 4 (mMCP-4), the murine functional analog to the human chymase, is a serine protease synthesized and stored in mast cell secretory granules. Our previous studies reported physiologic and pathologic roles for mMCP-4 in the maturation and synthesis of the vasoactive peptide endothelin-1 (ET-1) from its precursor, big ET-1. The aim of this study was to investigate the impact of mast cell degranulation or stabilization on mMCP-4–dependent pressor responses after the administration of big ET-1 or angiotensin I (Ang I). In anesthetized mice, mast cell degranulation induced by compound 48/80 (C48/80) or stabilization by cromolyn enhanced or repressed, respectively, the dose-dependent vasopressor responses to big ET-1 in wild-type (WT) mice but not in mMCP-4 knockout mice in a chymase inhibitor (TY-51469)–sensitive fashion. In addition, mMCP-4–dependent hydrolysis of the fluorogenic substrate Suc-Leu-Leu-Val-Tyr–7-amino-4-methylcoumarin was depleted or enhanced in peritoneal mast cells isolated from mice pretreated with C48/80 or cromolyn, respectively. Furthermore, C48/80 or cromolyn markedly increased or abolished, respectively, ET-1 (1–31) conversion from exogenous big ET-1 in WT mice peritoneal fluid–isolated mast cells, in vitro. Finally, the vasopressor responses to Ang I were unaffected by mast cell activation or stabilization, whereas those induced by the angiotensin-converting enzyme-resistant Ang I analog, [Pro11, D-Ala12] Ang I, were potentiated by C48/80. Altogether, the present study shows that mast cell activation enhances the mMCP-4–dependent vasoactive properties of big ET-1 but not Ang I in the mouse model.SIGNIFICANCE STATEMENT The current work demonstrates a significant role for mast cell stability in the cardiovascular pharmacology of big endothelin-1 but not angiotensin I in the murine systemic circulation.