Mast cell mediators increase endothelial cell MMP‐2 production in a β‐catenin‐dependent manner

Abstract

In skeletal muscle, mast cells reside in close proximity to capillaries and may be activated in response to muscle stretch. Angiogenesis may be initiated by factors released from mast cells including vascular endothelial growth factor (VEGF) and histamine. Both VEGF and histamine increase endothelial permeability, and as our results show, regulate matrix metalloproteinase (MMP)‐2 production and induce nuclear translocation of β‐catenin. Our objective is to determine how VEGF and histamine increase MMP‐2 production in endothelial cells isolated from the fat pad of rats. We have found that histamine acts through its H2 receptor as stimulation with the H2 receptor agonist dimaprit induced a significant increase in MMP‐2 mRNA levels and promoter activity (4.1±0.5 vs control, p< 0.05, n=3, 1.4±0.1 vs control, p<0.05, n=3). To determine if β‐catenin mediates transcription of MMP‐2, rat endothelial cells were transduced with Ad‐ICAT or Ad‐Bgal prior to growth factor stimulation. Transduction of ICAT blocked the VEGF induced increase in MMP‐2 mRNA levels (1.8±0.04 VEGF vs 1.0 for Bgal, p<0.05 n=3, 0.95±0.1 ICAT + VEGF vs Bgal, p<0.05 n=3). These results indicate a role for β‐catenin in the induction of endothelial cell MMP‐2 expression following VEGF and histamine stimulation. Funding by NSERC.