Fibrin and Collagen Differentially but Synergistically Regulate Sprout Angiogenesis of Human Dermal Microvascular Endothelial Cells in 3-Dimensional Matrix

Angiogenesis is a highly regulated event involving complex, dynamic interactions between microvascular endothelial cells and extracellular matrix (ECM) proteins. Alteration of ECM composition and architecture is a hallmark feature of wound clot and tumor stroma. We previously reported that during angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. However, the role of 3D ECM in the regulation of angiogenesis associated with wound healing and tumor growth is not well defined. This study investigates the correlation of sprout angiogenesis and ECM microenvironment using in vivo and in vitro 3D angiogenesis models. It demonstrates that fibrin and type I collagen 3D matrices differentially but synergistically regulate sprout angiogenesis. Thus blocking both integrin alpha v beta 3 and integrin alpha 2 beta 1 might be a novel strategy to synergistically block sprout angiogenesis in solid tumors. 1. Introduction Angiogenesis, the development of new blood vessels from preexisting vessels, is critical for a wide array of complex normal and pathological processes including morphogenesis, wound healing, and tumor growth [1]. Under normal physiologic conditions, angiogenesis is well controlled by the local balance between endogenous angiogenesis stimulators and angiogenesis inhibitors, although the regulatory mechanism is still not clearly defined. Sustained tumor angiogenesis is one of the hallmark features of solid tumor development. It is essential for tumor development and tumor metastasis. Almost four decades ago Dr. Judah Folkman pioneered the strategy of stopping tumor growth and metastasis by blocking tumor angiogenesis. With the 2004 FDA approval of bevacizumab (Avastin), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), to treat metastatic colorectal cancer in combination with 5-fluorouracil (5-FU), antiangiogenesis therapy has emerged as an essential new strategy for cancer treatment [2]. Angiogenesis is a highly regulated event that involves complex, dynamic interactions between microvascular endothelial cells and ECM proteins. In developing capillary sprouts, endothelial cells digest the surrounding extracellular matrix (ECM) and invade the matrix as a cylindrical aggregate of cells. These events clearly require an integrated response of endothelial cells to angiogenic factors and ECM proteins [3]. Alteration of ECM