Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer

Welti, Jonathan; Loges, Sonja; Dimmeler, Stefanie; Carmeliet, Peter

doi:10.1172/jci70212

Cited by 543 publications

(477 citation statements)

References 164 publications

(167 reference statements)

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“…Development of functional and mature blood vessel networks in implantable engineered tissues is fundamental to effective application of tissue engineering techniques toward treatment of a diversity of diseases, such as ischemia and cancer (29,30). Therefore, much contemporary research focuses on exploring the molecular determinants of the vasculogenesis and angiogenesis processes (31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Morphogenesis of 3D vascular networks is regulated by tensile forces

Rosenfeld

Landau

Shandalov

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Discussionmentioning

confidence: 99%

Morphogenesis of 3D vascular networks is regulated by tensile forces

Rosenfeld

Landau

Shandalov

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…However, this vasculature was not stable and degraded faster when compared to the oscillatory stretched constructs (Figures 1C and 3C). In contrast, the higher levels of vessel‐initiating cytokines at later time points and the stabilizing cytokines such as angiopoitin1, which activates mural cells to attach to the forming vessels and which has an important role in maintaining vessel quiescence,17 indicate that these vessels reach higher maturation levels and thus are stable over longer time periods ( Figure 4 ). …”

Section: Resultsmentioning

confidence: 99%

“…As mural cell characteristics have been shown to have a major impact on vessel stabilization,17 we then examined mural cell differentiation within oscillatory stretched constructs. αSMA and PDGFR‐β are markers for fibroblasts differentiation into myo‐fibroblasts, and are indicators for vessel maturation 18.…”

Section: Resultsmentioning

confidence: 99%

“…These processes are facilitated by secretion of various cytokines. Angiopoietin (Ang) 1 stabilizes the vessel by tightening the contacts between the recruited mural cells and the ECs, thereby decreasing vessel leakiness 17, 30. Our results show higher secretion of Ang1 in the oscillatory stretched group, suggesting that this mechanical stimulation increases vessel stability.…”

Section: Discussionmentioning

confidence: 99%

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

2018

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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.

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“…This multistage process is essential for cancer progression above 2-3 mm 3 [27]. Furthermore, the invasiveness of cancer depends on forming new vessels inside the tumor [28]. The proangiogenic effect of the main angiogenesis stimulating factor -VEGF results from VEGFR-2 activation, whereas the role of VEGFR-1 is not fully recognized yet [9,10,12].…”

Section: Discussionmentioning

confidence: 99%