TIMP‐1 is increased by shear stress in the skeletal muscle microvasculature

Abstract

Luminal splitting via internal division of capillaries is a form of angiogenesis caused by increased shear stress. A feature of luminal splitting is a lack of extracellular matrix proteolysis, which correlates with a decreased production of matrix metalloproteinase‐2 (MMP‐2). We hypothesized that the MMP inhibitor, tissue inhibitor of matrix metalloproteinase‐1 (TIMP‐1), is upregulated in response to shear stress. TIMP‐1 mRNA expression increased 3.8‐fold in the EDL of prasozin‐treated rats (p<0.05, n=4). Skeletal muscle endothelial cells were exposed to 2, 4, or 24 hours of shear stress (12 dyne/cm2). TIMP‐1 mRNA expression increased 7.0 and 9.0‐fold in cells after 2 and 24 hours of exposure to shear stress respectively (p<0.05, n=3), and TIMP‐1 protein increased 1.5 and 2.2‐fold after 2 and 24 hours of shear stress (p<0.05, n=3). TIMP‐1‐mediated inhibition of MMP‐2 also was increased 1.5 and 1.3‐fold after 2 and 24 hours of shear stress (n=2 and p<0.05, n=3 respectively). Our results show that TIMP‐1 is upregulated by shear stress, and suggest a mechanism for the absence of extracellular matrix proteolysis observed during luminal splitting.Funded by the Heart and Stroke Foundation of Canada.