The Interplay between Biomechanical and Biochemical Factors Regulates Lumen Formation and Navigation of Endothelial Cell Sprouts

摘要

Angiogenesis is the process of forming new blood vessels that originate from pre-existing vessels. In early angiogenesis stages, endothelial cells (ECs) migrate from the lumen of developed blood vessels into the surrounding extracellular matrix (ECM). Through the coordinated actions of migration and proliferation, these ECs organize into tubular capillary-like structures called sprouts. In this study, 3D EC sprout formation was examined using a microfluidic device that enabled the separate and simultaneous tuning of biomechanical and biochemical stimuli (Fig. 1). While previous investigations have been performed on each of these factors individually~(1,2), more recent studies have identified a critical interplay between the simultaneous effects of these two factors~3. For example, we previously studied 2D EC chemotaxis in response to vascular endothelial growth factor (VEGF) gradients in the absence of biomechanical stimulation.~4 In developing a model that enables precise specification of biochemical and biomechanical cues, we utilized a protocol that enables ECs to undergo a transition from the 2D to 3D culture environment mimicking angiogenic sprouting. Here we quantified the relative importance and combined consequences of discrete changes in matrix density, growth factor concentration, and growth factor gradient steepness during the stages of early sprout initiation, sprout elongation, sprout navigation, and lumen formation.