Inhibition of Fibroblast-Induced Angiogenic Phenotype of Cultured Endothelial Cells by the Overexpression of Tissue Inhibitor of Metalloproteinase (TIMP)-3

Abstract

In this study, we examined the effect of overexpression of tissue inhibitor of metalloproteinase (TIMP)-3 on the angiogenic phenotype expressed by vascular endothelial cells (ECs). ECs were infected with a recombinant adenovirus carrying the TIMP-3 gene at various multiplicities of infection, and TIMP-3 expression by transfected cells was confirmed by Western blotting and reverse zymography. At transfection doses of 6.25, 12.5, 25, 50 and 100 multiplicity of infection, EC migration was reduced to 66, 45, 25, 17 and 5%, respectively, of that of the control. At the multiplicity of infection of 20, capillary tube length was reduced by 80% compared to that of the control. Thus, expression of TIMP-3 by ECs effectively inhibited EC migration and tube formation. Overexpression of TIMP-3 by ECs may be considered a gene therapy strategy for the treatment of pathological angiogenesis such as cancer and diabetic retinopathy.

Genetic comparison of mouse lung telocytes with mesenchymal stem cells and fibroblasts

“…Remarkably, two main components of basement membrane, Collagen type IV and Nidogen 1 are up-regulated in the cultured TCs comparing with both MSCs and fibroblasts. Moreover, TIMP3 is an extracellular matrix-anchored metalloproteinase inhibitor that acts specifically to increase vascular (endothelial) basement membrane stability [36,37]. As TCs express Matrix Metalloproteases Mmp3 and Mmp10 also, it is likely that TCs are involved in both basement membrane assembly (stability) and surrounding extracellular matrix remodelling.…”

TIMP-3 as a therapeutic target for cancer

“…17 TIMP-3 also acts as a potential antiangiogenesis agent by inhibiting endothelial cell tube formation. 18 Moreover, TIMP-3 can inhibit cancer cell migration, invasion, and metastasis in vitro and in vivo . 19,20 Clinical studies have reported reduced TIMP-3 expression in cases of several cancer types compared with normal controls; 19–22 the loss of TIMP-3 may lead to poor outcomes, including large tumor size, high tumor stage, and metastasis.…”