Angiogenesis from endothelial progenitor cells is co‐regulated by vascular endothelial growth factor and matrix stiffness.

Abstract

Angiogenesis from endothelial progenitor cells is co‐regulated by vascular endothelial growth factor and matrix stiffness. Endothelial Progenitor Cells (EPCs) in the circulatory system have been suggested to maintain vascular homeostatis and contribute to adult vascular regeneration. These processes require that EPCs break down the extracellular matrix (ECM), migrate, differentiate into endothelial cells, and line the lumen of the blood vessels. Evidently the ECM plays a critical role by providing biochemical and biophysical cues that regulate cellular behavior. Using our controllable in vitro model of angiogenesis we show that vascular endothelial growth factor (VEGF) and matrix stiffness regulate angiogenesis from EPCs. When exposed to low levels of VEGF, EPCs proliferate independently of matrix stiffness. Exposure to high VEGF concentrations results in upregulation of MMPs, demonstrating EPCs migratory and invasive abilities. Under these conditions, the stiffness of the matrix affects the progression of angiogenesis. Immunofluorescence and TEM images confirm the formation of vacuoles, which fully develop into lumen within a chain elongated cell on the softest matrix. RNAi studies further suggest that EPCs sense matrix stiffness through signaling cascades downstream of integrin ligation leading to the activation of the RhoGTPase and Cdc42. These results suggest that dual regulation of VEGF and matrix compliances are required to modulate angiogenesis dynamics of EPCs.Grant Funding SourceAHA