Extracellular matrix compression temporally regulates microvascular angiogenesis

Abstract

Mechanical cues influence tissue regeneration, and although vasculature is known to be mechanically sensitive, little is known about the effects of bulk extracellular matrix deformation on the nascent vessel networks found in healing tissues. Previously, we found that dynamic matrix compression in vivo potently regulated revascularization during bone tissue regeneration; however, whether matrix deformations directly regulate angiogenesis remained unknown. Here, we demonstrated that load initiation time, magnitude, and mode all regulate microvascular growth, as well as upstream angiogenic and mechanotransduction signaling pathways. Immediate load initiation inhibited angiogenesis and expression of early sprout tip cell selection genes, while delayed loading enhanced microvascular network formation and upstream signaling pathways. This research provides foundational understanding of how extracellular matrix mechanics regulate angiogenesis and has critical implications for clinical translation of new regenerative medicine therapies and physical rehabilitation strategies designed to enhance revascularization during tissue regeneration.

Effect of cyclic mechanical loading on immunoinflammatory microenvironment in biofabricating hydroxyapatite scaffold for bone regeneration

“…Previously, using dynamic compression to investigate the effects of ECM deformations on the regulation of angiogenesis during bone tissue regeneration, Ruehle et al found that the expression of inflammation-related genes ( Cxcl 12, Tnf ) was significantly downregulated and the expression of regeneration-related genes ( Bmp2, Col 1a1 and Vegfa ) was upregulated by mechanical loading [ 50 ]. Mechanical stimuli also provide critical cues for MSCs residing at the vascular interface in terms of the effects of antioxidation and anti-inflammation [ 51 ].…”

Mechanical Stimulation on Mesenchymal Stem Cells and Surrounding Microenvironments in Bone Regeneration: Regulations and Applications

“…Following growth of blood vessels, the cartilage is gradually replaced by bone tissue. Joe's laboratory investigated the effects of immediate and delayed mechanical loading on vascular ingrowth in bone regeneration (Boerckel et al, 2011;Ruehle et al, 2020). The results showed that load initiation was a key determinant of vascular network formation.…”

“…Organs of the locomotor system undertake continuous mechanical loading, including compression on the bone, the stretch on muscles, and the fluid shear stress on blood vessels. Mechanical stimulation with different amplitudes, modalities, and durations plays an essential role in cell growth and differentiation, providing the possibility to regulate the lineage commitment of stem cells (Horner et al, 2019;McDermott et al, 2019;Ruehle et al, 2020). Mechanobiology is an emerging field specializing in the cellular response to mechanical cues, including the reception of mechanical signals and transduction of extracellular mechanical signals into intracellular biological signals (Fu et al, 2020).…”

Supramolecular Biopolymers for Tissue Engineering

“…To be more specific, we will briefly talk about vascularization, which is needed to irrigate thick constructs, as diffusion is not optimal for mass transfer over large distances (>200 μm) [152,153]. Vascularization is a process mainly dependent on cell-ECM interactions [154][155][156][157]. One of the current approaches to solve this issue was the synthesis of a self-assembling glycosylated peptide used to mimic the highly glycosylated environment of the ECM.…”