Interstitial flow mechanotransduction modulates vascular SMC motility and phenotype via heparan sulfate proteoglycan‐mediated FAK‐ERK activation in 3D

Interstitial flow directly affects cells in the tissue interstitium and regulates tissue physiology and pathology by modulating cell proliferation, differentiation, and migration. Previously we have shown that interstitial flow may be involved in vascular lesion formation after vascular injury. However, the structures and signaling pathways that vascular smooth muscle cells (SMCs) utilize to sense flow in a 3‐dimensional (3D) environment have not yet been elucidated. Here, we focused on uncovering the flow‐induced mechanotransduction mechanism in 3D. Interstitial flow induced ERK1/2 activation, promoted SMC migration and suppressed SMC marker expression. Disruption of heparan sulfate proteoglycan (HSPG) suppressed flow‐induced ERK1/2 activation and cell motility, and reversed SMC marker expression. Inhibition of focal adhesion kinase (FAK) also blocked flow‐induced ERK activation and cell motility. Flow induced FAK phosphorylation at Tyr925, and this activation was blocked when HSPGs were disrupted. In addition, cells could not sense flow after β1 integrins were blocked. We propose a mechanotransduction model wherein cell surface HSPGs, with the synergism of integrin, sense interstitial flow and activate the FAK‐ERK pathway, promoting cell motility and phenotype switching. This is the first study to describe a flow‐induced mechanotransduction mechanism in 3D. This study will be of interest in understanding the flow‐related mechanobiology in vascular lesion formation and also has implications in tissue engineering and cancer metastasis. Supported by NIH RO1 HL 57093 and 094889.