C‐Type Natriuretic Peptide as Mediator of an Endothelial Cell to Mast Cell Communication

Abstract

Mast cells (MC) play a critical role in leukocyte recruitment to sites of inflammation after ischemia/reperfusion (I/R). They reside in the perivascular tissue and release proteases and chemokines having detrimental effects on their immediate surroundings, such as endothelial cells. The triggers and counterregulators of MC activation are still enigmatic. We investigated whether endothelial C‐type natriuretic peptide (CNP) via its cGMP forming guanylyl cyclase B (GC‐B) receptor modulates the activity of MC and inflammation after I/R.Intravital microscopy was used to visualize the microcirculation within the cremaster muscle of anesthetized mice. Blood flow was temporally blocked for 30 min of ischemia. FITC‐Dextran was used to quantify macromolecule leakage during reperfusion. Ruthenium Red was used to stain perivascular degranulated MC. I/R provoked marked degranulation of perivascular resident MC (~7‐fold vs controls) and prominent leakage of FITC‐Dextran from postcapillary venules to the adjacent interstitial space. Local superfusion of CNP during reperfusion, significantly reduced the number of degranulated MC (to ~1.8‐fold vs controls) and concomitantly prevented vascular leakage. These effects were mimicked by the membrane‐permeable cGMP analog, 8‐bromo cGMP. In cultured murine bone marrow and human MC CNP activated GC‐B/cGMP signaling and cGMP protein kinase I‐dependent phosphorylation of the cytoskeleton‐associated vasoactive stimulated phosphoprotein (VASP) at Ser237.Our study indicates that the endothelial peptide CNP inhibits I/R‐induced degranulation of perivascular MC and thereby attenuates microvascular inflammation.Supported by SFB 688 and CHFC Würzburg