Publications in VIVO
 

Loskutoff, David J.

Faculty Member Emeritus
share the uri qr icon

Positions

Regulation of Cell Mediated Proteolysis by
Type 1 Plasminogen Activator Inhibitor


The activation of plasminogen provides an essential source of localized proteolytic activity for cells during tumor invasion, angiogenesis, cell migration, epithelial differentiation, ovulation, and for a variety of other physiologic events including the removal of pathological blood clots. Precise regulation of plasminogen activator (PA) activity is achieved through the action of type 1 PA inhibitor (PAI-1). PAI-1 itself is produced by a variety of cells and accumulates in their extracellular matrix (ECM) where it is bound to vitronectin (VN). Its synthesis is stimulated by growth factors, cytokines and hormones. Our long-term objective is to define the cellular events that regulate PAI-1 synthesis, secretion, and activity by using biochemical, cellular, and molecular biological approaches to study cultured endothelial cells, murine models of human disease, and human vascular tissue. One current focus of our studies is to define the interaction between PAI-1 and VN, and to delineate how these interactions regulate PAI-1 activity. The mechanisms by which PAI-1 modulates integrin-independent and dependent cell adhesion also are being investigated. A second area of interest involves the mechanisms by which insulin, transforming growth factor, and tumor necrosis factor elevate PAI-1 gene expression both in normal and obese mice, and in various insulin-resistant states. The tissues and cells that produce PAI-1 mRNA and protein in vivo in the obese mouse and in human atherosclerotic tissue are being studied by using competitive PCR assays as well as in situ hybridization analysis. Finally, the contribution of PAI-1, VN and leptin to thrombus formation and dissolution, to vascular remodeling after injury (restenosis), and to angiogenesis, is being investigated in knockout mice lacking specific genes. These studies should lead to a better understanding of PAI-1 and its role in the pathogenesis of human vascular disease.

recent publications