Table 6.3.

Prominent mechanosensory pathways in tumor angiogenesis

Mechanosensor	Location	Mechanical activation	Relevant function	Role in tumor angiogenesis	References
PECAM1	Adherens junctions, apicolateral membrane	Fluid shear stress, circumferential strain	Phosphorylated in response to mechanical forces, transactivates VEGFR	Important in changes to cytoskeletal architecture. Activates VEGFR and downstream signaling events	[114, 146, 147, 149, 151]
VE-cadherin	Adherens junctions	Fluid shear stress, circumferential strain	Transmembrane scaffolding of PECAM1 and VEGFR2/3. Important in maintaining barrier function	Disrupted VE-cadherin endothelial cell-cell junctions are observed in stiff environments and tumor vasculature	[12, 113, 114, 152, 156]
VEGFR2	Adherens junctions, apical membrane	Fluid shear stress, circumferential strain	Shear stress causes ligand-independent phosphorylation, activates MAPK/PI3K/Akt	Elevated expression in tumor blood vessels. Involved in tumor EC barrier integrity. Major signal transducer for angiogenesis	[147, 149, 157–159]
VEGFR3	Adherens junctions, apical membrane	Fluid shear stress, circumferential strain	Shear stress causes ligand-independent phosphorylation, activates MAPK/PI3K/Akt	Involved in maintaining tumor EC barrier integrity. Inhibition reduces vascular density	[149, 160, 161]
Integrins	Basal adhesion complexes	Fluid shear stress, cell-ECM stress	Shear stress causes downstream activation by PI3K to regulate cell orientation. Important in sensing and applying cell-ECM stresses	Inhibition of α1β1 and α2β1, α5β1, as well as αvβ5 and αvβ3 suppress tumor angiogenesis. αvβ3 and αvβ5 integrin expression linked to grade of neuroblastoma	[117, 126, 130–133, 141]
Actin cytoskeleton	Cortical plasma membrane, cytoplasmic, perinuclear	Fluid shear stress, circumferential strain, cell-ECM stress	Fluid shear stress causes filament deformations. Inhibition blocks many responses to mechanical cues	Tumor endothelial cells demonstrate increased cellular contractility and aberrant mechanosensitivity	[80, 113, 116–118]
TRPV4	Apical membrane	Fluid shear stress, circumferential strain	Regulates mechanosensitivity and Rho/ROCK activity	Tumor endothelial cells have reduced TRPV4 expression, leading to aberrant Rho/ROCK mechanosensitivity	[122, 174–176]
EP2	Apical/basal membrane	Fluid shear stress, cell-ECM stress	Induces VEGF expression via ERK2/JNK1 activation	Released from cancer cells to elicit a pro-angiogenic response	[178, 179, 181]
S1PR	Apical/basal membrane	Fluid shear stress, cell-ECM stress	Activation leads to Rac-Cdc42 signaling and correlates with ERK1 and ERK2 activation	Important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation, and vascular maturation	[178, 179, 182]
PAR1	Apical/basal membrane	Fluid shear stress, cell-ECM stress	Modulates Rho GTPase activity	Influences endothelial cell permeability. PAR1 expression increased in cancer	[178, 179, 183, 184]