Blood Coagulation and Blood Vessel Development

Abstract

In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , Arderiu et al1 investigate the role of tissue factor (TF) in angiogenesis using both in vitro and in vivo models. They find that TF expression in endothelial cells (ECs) stimulates the expression of chemokine ligand 2 (CCL2). This facilitates the recruitment of vascular smooth muscle cells (VSMCs) and the stabilization of EC-VSMC networks. See accompanying article on page 2607 Judah Folkman, a pioneer in angiogenesis research, was intrigued by the connection between blood coagulation and blood vessel development and proposed that the 2 processes were intimately connected.2,3 A summary of the key observations connecting TF and angiogenesis is shown in the Figure. In 1994, Zhang and colleagues4 were the first to show that TF expression by Meth-A sarcoma cells regulates their angiogenic activity in vivo. A high level of TF expression was associated with enhanced expression of the proangiogenic factor vascular EC growth factor. Later, Yu et al5 demonstrated that antisense silencing of TF expression in a human colorectal cancer cell line reduced the growth of tumors in mice. A study with human MDA-MB-231 breast cancer cells revealed that the TF/factor VIIa complex regulated the expression of interleukin-8, another angiogenic factor, via activation of protease-activated receptor 2 (PAR2).6 Interestingly, the transcriptional program induced by activation of PAR2 was similar to that induced by activation of the thrombin receptor PAR1 and included many angiogenic factors and chemokines.7 A summary of the proposed coagulation protease-PAR pathways that lead to the expression of angiogenic factors by tumors cells is shown in panel A of the Figure. One area of controversy is whether TF is expressed by ECs within tumors. One study8 reported TF expression by ECs in invasive breast cancer but not …