Spatial Configurations of 3D Extracellular Matrix Collagen Density and Anisotropy Simultaneously Guide Angiogenesis

Extracellular matrix (ECM) collagen density and fibril anisotropy are thought to affect the development of new vasculatures during pathologic and homeostatic angiogenesis. Computational simulation is emerging as a tool to investigate the role of matrix structural configurations on cell guidance. However, prior computational models have only considered the orientation of collagen as a model input. Recent experimental evidence indicates that cell guidance is simultaneously influenced by the direction and intensity of alignment (i.e., degree of anisotropy) as well as the local collagen density. The objective of this study was to explore the role of ECM collagen anisotropy and density during sprouting angiogenesis through simulation in the AngioFE and FEBio modeling frameworks. AngioFE is a plugin for FEBio (Finite Elements for Biomechanics) that simulates cell-matrix interactions during sprouting angiogenesis. We extended AngioFE to represent ECM collagen as deformable 3D ellipsoidal fibril distributions (EFDs). The rate and direction of microvessel growth were modified to depend simultaneously on the ECM collagen anisotropy (orientation and degree of anisotropy) and density. The sensitivity of growing neovessels to these stimuli was adjusted so that AngioFE could reproduce the growth and guidance observed in experiments where microvessels were cultured in collagen gels of varying anisotropy and density. We then compared outcomes from simulations using EFDs to simulations that used AngioFE’s prior vector field representation of collagen anisotropy. We found that EFD simulations were more accurate than vector field simulations in predicting experimentally observed microvessel guidance. Predictive simulations demonstrated the ability of anisotropy gradients to recruit microvessels across short and long distances relevant to wound healing. Further, simulations predicted that collagen alignment could enable microvessels to overcome dense tissue interfaces such as tumor-associated collagen structures (TACS) found in desmoplasia and tumor-stroma interfaces. This approach can be generalized to other mechanobiological relationships during cell guidance phenomena in computational settings.Author summary: Matrix collagen fibril anisotropy and density are gaining recognition for their mechanoregulatory roles in cellular growth and guidance. For instance, we recently demonstrated that new vessel growth increases with the degree of matrix collagen alignment in a density-dependent manner during in vitro angiogenesis. The spatial configuration of collagen fibril alignment and density between adjacent tissues is thought to affect development of new vasculatures during pathologic and homeostatic angiogenesis. Computational simulation is emerging as a tool to evaluate how the integrated effects of different matrix structural cues are involved in guidance and deflection of microvessels between tissues. Thus, the objective of this study was to incorporate our prior experimental finding that angiogenic neovessels are simultaneously sensitive to ECM collagen density and fibril anisotropy (orientation and degree of anisotropy). We found that fibril anisotropy emboldens neovessels to migrate long distances and persist through dense tissue interfaces. These findings have implications for angiogenesis during wound healing and pathologies such as cancer tumorigenesis.