Morphogenesis of 3D vascular networks is regulated by tensile forces

Abstract

Understanding the forces controlling vascular network properties and morphology can enhance in vitro tissue vascularization and graft integration prospects. This work assessed the effect of uniaxial cell-induced and externally applied tensile forces on the morphology of vascular networks formed within fibroblast and endothelial cell-embedded 3D polymeric constructs. Force intensity correlated with network quality, as verified by inhibition of force and of angiogenesis-related regulators. Tensile forces during vessel formation resulted in parallel vessel orientation under static stretching and diagonal orientation under cyclic stretching, supported by angiogenic factors secreted in response to each stretch protocol. Implantation of scaffolds bearing network orientations matching those of host abdominal muscle tissue improved graft integration and the mechanical properties of the implantation site, a critical factor in repair of defects in this area. This study demonstrates the regulatory role of forces in angiogenesis and their capacities in vessel structure manipulation, which can be exploited to improve scaffolds for tissue repair.

Forces and mechanotransduction in 3D vascular biology

“…The first studies using these 3D in vitro microfluidic vessel models have focused on confirming many force-driven cell behavior observations made in in vivo and 2D culture: increased barrier function and junctional reorganization in response to elevated shear stress [53], changes in transmural pressure affect vessel permeability, sprouting, and monolayer integrity [54-56], and alterations in ECM stiffness dictate flow responsiveness and vessel barrier function [41,43]. Studies in 3D ex vivo and in vitro vascular beds have demonstrated that application of bulk tensile stress to alter 3D ECM mechanical properties can regulate neovessel sprouting, elongation during angiogenesis, and vascular network organization [57,58]. …”

Obstacles and challenges for tissue engineering and regenerative medicine: Australian nuances

“…The ECM composition can also influence the efficacy of revascularisation as demonstrated when scaffolds combined with tropoelastin (that is responsible for elasticity of blood vessels) were implanted into mouse abdominal muscle, resulting in enhanced perfusion of the penetrating vasculature and improved integration . The importance of tensile forces in angiogenesis and improved vessel structure for tissue repair is also demonstrated . Real time monitoring of revascularisation in vivo of (small) tissue engineered skeletal muscle implants (donor neonatal rat muscles into nude immunocompromised host mice) using a mouse dorsal window implantation model, showed a steady ingrowth of blood‐perfused (host) microvasculature with increasing force contraction over 2 weeks .…”

“…53 The importance of tensile forces in angiogenesis and improved vessel structure for tissue repair is also demonstrated. 54 Real time monitoring of revascularisation in vivo of (small) tissue engineered skeletal muscle implants (donor neonatal rat muscles into nude immunocompromised host mice) using a mouse dorsal window implantation model, showed a steady ingrowth of blood-perfused (host) microvasculature with increasing force contraction over 2 weeks. 55 The importance of a robust vascular supply for successful translation is also emphasised for scaled-up cardiac tissue engineering for clinical treatment of heart failure.…”

Creating to understand – developmental biology meets engineering in Paris

“…Shulamit Levenberg (Technion, Israel) and others have previously shown that this can be achieved by inducing the in vitro organization of endothelial cells within engineered muscle (Levenberg et al, 2005), pancreatic (KaufmanFrancis et al, 2012) or bone (Rivron et al, 2012a) tissues. She now showed how cell-induced and externally applied tensile forces pattern the behavior of endothelial networks (Rosenfeld et al, 2016). In addition to its classical transport function, the vasculature also provides cues for the development and patterning of organs (Red-Horse et al, 2007).…”