Heparin Inhibits Proliferation and Migration of Patient-Derived Vascular Cells Only at Non-physiological Concentrations Due to Antagonistic Pathways

Abstract

Aims: Experimental animal models have demonstrated inhibition of intimal hyperplasia processes by heparin. These effects have not been observed in clinical trials. Diverging experimental conditions are the most conspicuous reasons. This study was designed to test if heparin inhibits intimal hyperplasia processes on patient-derived vascular cells at clinically relevant concentrations. Study Design: Comparison of heparin effects on patient-derived vascular cells in culture. Place and Duration of Study: Department of Biomedicine, University of Bergen, Norway between 2012 and 2014. Methodology: Vascular cells isolated from patient biopsies were treated with heparin and evaluated for effects on proliferation, migration and cell signaling using image based cell enumeration, real time migration monitoring and flow cytometry. Results: Reduced proliferation and migration in vascular cell cultures could only be detected after addition of high non-physiological heparin concentrations. In cultures stimulated by human fibroblast growth factor (hFGF), mitogen-activated protein kinase extracellular signal-regulated kinase (MAPK-ERK) phosphorylation was increased at lower heparin concentrations, while it was reduced dose-dependently by heparin in unstimulated cultures. Conclusion: Heparin inhibits intimal hyperplasia processes in patient-derived VSMC cultures, but only at concentrations exceeding clinical doses. This is due to an increased MAPK-ERK phosphorylation at lower heparin concentrations in the presence of hFGF. MAPK-ERK phosphorylation was influenced by heparin through both inhibitory and stimulatory pathways. These findings can explain the divergence of results between previous in vitro and clinical studies and provide a basis for new therapeutic strategies.