43
membrane receptor tension results in modification of cellular biochemistry, which
eventually impacts cell growth and motility and overall network patterning [20].
Another work showed that tensile forces generated by ECs cause ECM alignment,
leading to sprout alignment [26]. In contrast, Ceccarelli et al. claimed that vessel
alignment is caused by changes in ECM stiffness (resulting from the applied strain)
rather than ECM alignment [6]. Kaunas and Deguchi determined that cell alignment
in response to cyclic stretch is guided by remodeling of cell adhesions and actin
stress fibers, where myosin II has a major role in maintaining cellular homeostasis
under mechanically stimulated environments [22].
Strain was also shown to influence cytokine secretion from stimulated vascularized
constructs. Vascular endothelial growth factor (VEGF) and platelet-derived growth
factor (PDGF)-ββ secretion levels increased under cyclic strain when compared to the
unstimulated control group [45]. This correlates with another study that showed an
increase in angiopoietin 2 (Ang-2) and PDGF-ββ secretion from ECs subjected to
cyclic strain. Endothelial migration and sprout formation were both increased under
cyclic strain conditions [62]. Static strain has been shown to induce vessel formation,
without the need for addition of growth factors, and to stimulate muscle cells surrounding the ECs to secrete VEGF [54]. When subjecting tubular constructs composed of fibrin seeded with bovine aortic endothelial cells, to 7 days of 10% cyclic
strain, the length and density of the forming sprouts were affected; stimulated constructs displayed wider, less branched sprouts compared to the unstimulated control
group [14]. In addition, cyclic strain was shown to induce a short-term increase in
gene expression of collagen type I, fibronectin, and elastin within human pluripotent
stem cell-derived vSMCs. In the long term, uniaxial strain decreased ECM expression
within mature vSMCs, whereas in less mature vSMCs, elastin upregulation was found
[58]. Rho-associated kinase (ROCK) is shown to have an important role in vessel
alignment and remodeling under cyclic stretch. The addition of ROCK inhibitor to a
culture medium resulted in alignment suppression and a decrease in vessel sprouting.
In contrast, inhibition of the receptor tyrosine kinase resulted in a decrease in vessel
sprout density but had no effect on vessel alignment [59].
Stretch has also been utilized in the field of tissue engineering of large blood vessels. A special bioreactor was developed to enable application of cyclic biaxial
stretch on polyglycolic acid (PGA) vessels seeded with SMCs, to mimic the stimulations in native arteries. Biaxial stretch-stimulated constructs formed elastic fibers
and aligned collagen fibers, similar to those found in native arteries, with higher
suture retention strength. Additionally, biaxial stretch stimulation was shown to
increase the strength and compliance of the engineered blood vessels [19].
2.3.2 Fluid Shear Stress
Flow-induced shear stress is correlated with morphological changes in endothelial
cells in vitro [17, 18, 39, 51] as well as with changes in gene, protein, and miRNA
expression [15, 40]. In microfluidic devices [3, 13, 21, 55] and two-dimensional
(2D) monolayer “flow-over” models [2, 56], flow-induced shear stress has been
2 Mechanical Regulation of Vascularization in Three-Dimensional Engineered Tissues
membrane receptor tension results in modification of cellular biochemistry, which
eventually impacts cell growth and motility and overall network patterning [20].
Another work showed that tensile forces generated by ECs cause ECM alignment,
leading to sprout alignment [26]. In contrast, Ceccarelli et al. claimed that vessel
alignment is caused by changes in ECM stiffness (resulting from the applied strain)
rather than ECM alignment [6]. Kaunas and Deguchi determined that cell alignment
in response to cyclic stretch is guided by remodeling of cell adhesions and actin
stress fibers, where myosin II has a major role in maintaining cellular homeostasis
under mechanically stimulated environments [22].
Strain was also shown to influence cytokine secretion from stimulated vascularized
constructs. Vascular endothelial growth factor (VEGF) and platelet-derived growth
factor (PDGF)-ββ secretion levels increased under cyclic strain when compared to the
unstimulated control group [45]. This correlates with another study that showed an
increase in angiopoietin 2 (Ang-2) and PDGF-ββ secretion from ECs subjected to
cyclic strain. Endothelial migration and sprout formation were both increased under
cyclic strain conditions [62]. Static strain has been shown to induce vessel formation,
without the need for addition of growth factors, and to stimulate muscle cells surrounding the ECs to secrete VEGF [54]. When subjecting tubular constructs composed of fibrin seeded with bovine aortic endothelial cells, to 7 days of 10% cyclic
strain, the length and density of the forming sprouts were affected; stimulated constructs displayed wider, less branched sprouts compared to the unstimulated control
group [14]. In addition, cyclic strain was shown to induce a short-term increase in
gene expression of collagen type I, fibronectin, and elastin within human pluripotent
stem cell-derived vSMCs. In the long term, uniaxial strain decreased ECM expression
within mature vSMCs, whereas in less mature vSMCs, elastin upregulation was found
[58]. Rho-associated kinase (ROCK) is shown to have an important role in vessel
alignment and remodeling under cyclic stretch. The addition of ROCK inhibitor to a
culture medium resulted in alignment suppression and a decrease in vessel sprouting.
In contrast, inhibition of the receptor tyrosine kinase resulted in a decrease in vessel
sprout density but had no effect on vessel alignment [59].
Stretch has also been utilized in the field of tissue engineering of large blood vessels. A special bioreactor was developed to enable application of cyclic biaxial
stretch on polyglycolic acid (PGA) vessels seeded with SMCs, to mimic the stimulations in native arteries. Biaxial stretch-stimulated constructs formed elastic fibers
and aligned collagen fibers, similar to those found in native arteries, with higher
suture retention strength. Additionally, biaxial stretch stimulation was shown to
increase the strength and compliance of the engineered blood vessels [19].
2.3.2 Fluid Shear Stress
Flow-induced shear stress is correlated with morphological changes in endothelial
cells in vitro [17, 18, 39, 51] as well as with changes in gene, protein, and miRNA
expression [15, 40]. In microfluidic devices [3, 13, 21, 55] and two-dimensional
(2D) monolayer “flow-over” models [2, 56], flow-induced shear stress has been
2 Mechanical Regulation of Vascularization in Three-Dimensional Engineered Tissues