Oscillatory Strain Promotes Vessel Stabilization and Alignment through Fibroblast YAP‐Mediated Mechanosensitivity

Abstract

Endothelial cells form the interior layer of blood vessels and, as such, are constantly exposed to shear stress and mechanical strain. While the impact of shear stress on angiogenesis is widely studied, the role of mechanical strain is less understood. To this end, endothelial cells and fibroblasts are cocultured under oscillatory strain to create a vessel network. The two cell types show distinctly different sensitivities to the mechanical stimulation. The fibroblasts, sense the stress directly, and respond by increased alignment, proliferation, differentiation, and migration, facilitated by YAP translocation into the nucleus. In contrast, the endothelial cells form aligned vessels by tracking fibroblast alignment. YAP inhibition in constructs under mechanical strain results in vessel destruction whereas less damage is observed in the YAP‐inhibited static control. Moreover, the mechanical stimulation enhances vessel development and stabilization. Additionally, vessel orientation is preserved upon implantation into a mouse dorsal window chamber and promotes the invading host vessels to orient in the same manner. This study sheds light on the mechanisms by which mechanical strain affects the development of blood vessels within engineered tissues. This can be further utilized to engineer a more organized and stable vasculature suitable for transplantation of engineered grafts.

Cardiac tissue engineering: state-of-the-art methods and outlook

“…Model of generation, alignment, and stabilization of spindle shaped fibroblasts and vessel under oscillatory stretch was also reported [149]. These results reveal a new mechanism for vessel network formation: under oscillatory strain, 3D scaffolds can promote mural cell alignment, cell proliferation, translocation of a mechanosensitive transcriptional activator (YAP) into cell nuclei, and increased expression levels of β-catenin.…”

“…Furthermore, ECs, which are tolerant to stretch stimulus, form aligned vessels directed by the fibroblast and ECM alignment. However, there is loss of fibroblast alignment and vessel alignment due to mechanical uncoupling of the cells after adding blebbistatin to the culture medium [149]. In addition, both fibroblasts and vessels lose alignment when the cellular proliferation and signaling pathways responding to mechanical stimulus are inhibited.…”

Albumin-Enriched Fibrin Hydrogel Embedded in Active Ferromagnetic Networks Improves Osteoblast Differentiation and Vascular Self-Organisation

“…Furthermore, the synergy between BMP-2 and VEGF has been reported [58], in which there is an intimate relation to bone development and healing that is advantageous for bone regeneration procedures. In 444_AF, the higher expression of Ang-1, which has an important role in maintaining vessel quiescence [59], and Ang-2, which is a vessel destabiliser [60] with an important role in vascular remodelling, may indicate that these vessels reached higher maturation levels and thus are stable over longer time periods. In both scaffolds, vWF gradually decreased from day 16 to 21 with lower expression levels for 444_AF (16 days: 0.5-fold, 21 days: 0.3-fold); however, significant differences between these groups were only detected at day 21 ( p < 0.05).…”

Albumin-Enriched Fibrin Hydrogel Embedded in Active Ferromagnetic Networks Improves Osteoblast Differentiation and Vascular Self-Organisation

“…bone development and healing that is advantageous for bone regeneration procedures. In 444_AF, the higher expression of Ang-1, which has an important role in maintaining vessel quiescence [57], and Ang-2, which is a vessel destabiliser [58] with an important role in vascular remodelling, may indicate that these vessels reached higher maturation levels and thus are stable over longer time periods. In both constructs, vWF gradually decreased from day 16 to 21 with lower expression levels for 444_AF (16 days: 0.5-fold, 21 days: 0.3-fold); however, significant differences between these groups were only detected at day 21 (p < 0.05).…”