Plasminogen mediates angiogenesis and wound healing by interaction with thrombomodulin

Abstract

The plasminogen activation system including plasminogen (Plg)/plasmin (Plm) urokinase-type plasminogen activator (uPA) and urokinase-type plasminogen activator receptor (uPAR) mainly controls pericellular proteolysis in angiogenesis and skin wound healing However the Plg receptor that participates in uPA-mediated Plg activation has not yet been identified In the first part of this study Ｉdemonstrated that thrombomodulin (TM) a type I transmembrane glycoprotein is a novel Plg receptor that plays a role in pericellular proteolysis and cell migration Plg activation at cell surface and the extent of its cell migration- and invasion-promoting effect are cellular TM expression dependent Direct binding of Plg and recombinant TM extracellular domain with a KD of 0 1 to 0 3 μM was determined through surface plasmon resonance analysis Colocalization of TM Plg and uPA receptor within plasma membrane lipid rafts at the leading edge of migrating endothelial cells was demonstrated and was also shown to overlap with areas of major pericellular proteolysis Moreover the roles of TM and Plg in neo-angiogenesis were demonstrated in vivo through the skin wound-healing model In the second part of this study I investigated the role of Plg/TM/uPAR complex in skin wound healing This complex was formed during early period of injured wound where the Plm production was promoted On the other hand the Plm production was decreased in wound healing of epidermal TM-knockout mice Plg could induce growth factors expression to increase cell migration and proliferation in a TM-dependent manner TM expression in keratinocytes was significantly down-regulated in hyperglycemic conditions resulting in decrease of cell migration and proliferation In addition Plg-induced growth factors expression were diminished in TM knockdown keratinocytes In conclusion TM/Plg in conjunction with uPA/uPAR complex may play a critical role in regulation of pericellular proteolytic activity during cell migration; furthermore this complex is responsible for the increase of growth factor expression that promotes keratinocyte migration and proliferation These findings provide a novel insight into Plg activation in regulating growth factors expression that may have therapeutic applications to treat acute or chronic wound

Date of Award	2014 Mar 10
Original language	English
Supervisor	Hua-Lin Wu (Supervisor)