2. Academic Validation
  3. Biomechanical stimulation promotes blood vessel growth despite VEGFR-2 inhibition

Biomechanical stimulation promotes blood vessel growth despite VEGFR-2 inhibition

  • BMC Biol. 2023 Dec 10;21(1):290. doi: 10.1186/s12915-023-01792-y.
Bronte Miller Johnson 1,  Allison McKenzie Johnson 1,  Michael Heim 1,  Molly Buckley 1,  Bryan Mortimer 2,  Joel L Berry 1 3,  Mary Kathryn Sewell-Loftin 4 5
Affiliations

Affiliations

  • 1 Department of Biomedical Engineering, University of Alabama at Birmingham, 1824 6th Avenue South, Wallace Tumor Institute, Room 630A, Birmingham, AL, 35294, USA.
  • 2 Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • 3 O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
  • 4 Department of Biomedical Engineering, University of Alabama at Birmingham, 1824 6th Avenue South, Wallace Tumor Institute, Room 630A, Birmingham, AL, 35294, USA. [email protected].
  • 5 O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA. [email protected].
PMID: 38072992 DOI: 10.1186/s12915-023-01792-y
Abstract

Background: Angiogenesis, or the growth of new vasculature from existing blood vessels, is widely considered a primary hallmark of Cancer progression. When a tumor is small, diffusion is sufficient to receive essential nutrients; however, as the tumor grows, a vascular supply is needed to deliver oxygen and nutrients into the increasing mass. Several anti-angiogenic Cancer therapies target VEGF and the receptor VEGFR-2, which are major promoters of blood vessel development. Unfortunately, many of these Cancer treatments fail to completely stop angiogenesis in the tumor microenvironment (TME). Since these therapies focus on the biochemical activation of VEGFR-2 via VEGF ligand binding, we propose that mechanical cues, particularly those found in the TME, may be a source of VEGFR-2 activation that promotes growth of blood vessel networks even in the presence of VEGF and VEGFR-2 inhibitors.

Results: In this paper, we analyzed phosphorylation patterns of VEGFR-2, particularly at Y1054/Y1059 and Y1214, stimulated via either VEGF or biomechanical stimulation in the form of tensile strains. Our results show prolonged and enhanced activation at both Y1054/Y1059 and Y1214 residues when endothelial cells were stimulated with strain, VEGF, or a combination of both. We also analyzed Src expression, which is downstream of VEGFR-2 and can be activated through strain or the presence of VEGF. Finally, we used fibrin gels and microfluidic devices as 3D microtissue models to simulate the TME. We determined that regions of mechanical strain promoted increased vessel growth, even with VEGFR-2 inhibition through SU5416.

Conclusions: Overall, understanding both the effects that biomechanical and biochemical stimuli have on VEGFR-2 activation and angiogenesis is an important factor in developing effective anti-angiogenic therapies. This paper shows that VEGFR-2 can be mechanically activated through strain, which likely contributes to increased angiogenesis in the TME. These proof-of-concept studies show that small molecular inhibitors of VEGFR-2 do not fully prevent angiogenesis in 3D TME models when mechanical strains are introduced.

Keywords

Angiogenesis; Endothelial cells; Mechanobiology; Strain; Tumor microenvironment; VEGF; VEGFR-2.

Figures
Products