The role of thrombin in angiogenesis

Abstract

The suggestion of the late Judah Folkman that solid tumors are angiogenesis-dependent in the 1970s stimulated a multidisciplinary research effort to understand the complex cascade of events involved in new blood vessel formation under physiological and pathological conditions. A plethora of endogenous modulators of angiogenesis has been identified, and their roles in the molecular and cellular events that mediate and regulate angiogenesis have been proposed. In addition, it has been recognized that besides solid tumors a large number of common diseases such as ocular diseases, inflammation, etc., have as underlying pathology the derangement of angiogenesis. This prompted a major effort of the biotechnology industry to identify targets and develop agents for the so called angiogenesis-based therapies. A brief overview of the regulation of angiogenesis and the clinical applications that have resulted thus far is presented. Furthermore, our finding that thrombin is a potent angiogenic mediator that may play a pivotal role in orchestrating angiogenic factors led us to summarize the recent findings on the role of the coagulation cascade and its components in angiogenesis. Thrombin is a promoter of angiogenesis by activating PAR1 receptors in platelet and endothelial cells. This identifies PAR1 as a target for inhibiting angiogenesis with potential therapeutic applications. In addition, thrombin plays a role in promoting angiogenesis by PAR1-independent mechanisms. Through its RGD sequence, thrombin serves as an adhesive and aptotactic factor for endothelial cells. Thrombin is a potent antiapoptotic factor for endothelial cells, pointing to a novel role of thrombin in vascular protection and integrity. The implications of these findings in the overall regulation of angiogenesis and their possible significance in pathological states are discussed.