title: Interstitial flow regulates the angiogenic response and phenotype of endothelial cells in a 3D culture model.
abstract: A crucial yet ill-defined phenomenon involved in the remodeling of vascular networks, including angiogenic sprouting, is flow-mediated endothelial dynamics and phenotype changes. Despite interstitial flow (IF) being ubiquitously present in living tissues surrounding blood capillaries, it is rarely investigated and poorly understood how endothelial cells respond to this flow during morphogenesis. Here we develop a microfluidic 3D in vitro model to investigate the role of IF during vasculogenic formation and angiogenic remodeling of microvascular networks. In the presented model, human blood endothelial cells co-cultured with stromal fibroblasts spontaneously organize into an interconnected microvascular network and then further expand to adjacent avascular regions in a manner of neovessel sprouting. We found that in the presence of IF, vasculogenic organization of the microvascular network was significantly facilitated regardless of the flow direction, whereas angiogenic sprouting was promoted only when the directions of flow and sprouting were opposite while angiogenic activity was suppressed into the direction of flow. We also observed that the vasculatures switch between active angiogenic remodeling and quiescent/non-sprouting state in the contexts provided by IF. This regulatory effect can be utilized to examine the role of anti-angiogenic compounds, clearly distinguishing the differential influences of the compounds depending on their mechanisms of action. Collectively, these results suggest that IF may serve as a critical regulator in tissue vascularization and pathological angiogenesis.
authors.affiliation: Mechanical Engineering, Seoul National University, Gwanak-gu, Seoul 08826, Korea. njeon@snu.ac.kr.
authors.forename: Sudong
authors.initials: S
authors.lastname: Kim
authors.affiliation: Mechanical Engineering, Seoul National University, Gwanak-gu, Seoul 08826, Korea. njeon@snu.ac.kr.
authors.forename: Minhwan
authors.identifier: 0000-0001-6720-7514
authors.initials: M
authors.lastname: Chung
authors.affiliation: Mechanical Engineering, Seoul National University, Gwanak-gu, Seoul 08826, Korea. njeon@snu.ac.kr.
authors.forename: Jungho
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Interdisciplinary Program for Bioengineering, Seoul National University, Gwanak-gu, Seoul 08826, Korea.
authors.forename: Somin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Mechanical Engineering, Seoul National University, Gwanak-gu, Seoul 08826, Korea. njeon@snu.ac.kr and Interdisciplinary Program for Bioengineering, Seoul National University, Gwanak-gu, Seoul 08826, Korea.
authors.forename: Noo Li
authors.initials: NL
authors.lastname: Jeon
mesh_terms: D060833:Cellular Microenvironment; D005109:Extracellular Matrix / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology*; D006801:Humans; D056656:Lab-On-A-Chip Devices; D018919:Neovascularization, Physiologic; D010641:Phenotype