title: Prelamin A Accumulation Attenuates Rac1 Activity and Increases the Intrinsic Migrational Persistence of Aged Vascular Smooth Muscle Cells.
abstract: Vascular smooth muscle cell (VSMC) motility is essential during both physiological and pathological vessel remodeling. Although ageing has emerged as a major risk factor in the development of cardiovascular disease, our understanding of the impact of ageing on VSMC motility remains limited. Prelamin A accumulation is known to drive VSMC ageing and we show that presenescent VSMCs, that have accumulated prelamin A, display increased focal adhesion dynamics, augmented migrational velocity/persistence and attenuated Rac1 activity. Importantly, prelamin A accumulation in proliferative VSMCs, induced by depletion of the prelamin A processing enzyme FACE1, recapitulated the focal adhesion, migrational persistence and Rac1 phenotypes observed in presenescent VSMCs. Moreover, lamin A/C-depleted VSMCs also display reduced Rac1 activity, suggesting that prelamin A influences Rac1 activity by interfering with lamin A/C function at the nuclear envelope. Taken together, these data demonstrate that lamin A/C maintains Rac1 activity in VSMCs and prelamin A disrupts lamin A/C function to reduce Rac1 activity and induce migrational persistence during VSMC ageing.
authors.affiliation: British Heart Foundation Centre of Research Excellence, Cardiovascular Division, King's College London, London SE5 9NU, UK. laurenjadeporter@gmail.com.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Porter
authors.affiliation: Randall Division of Cell and Molecular Biophysics, New Hunt's House, King's College London, London SE1 1UL, UK. mark_robert.holt@kcl.ac.uk.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Holt
authors.affiliation: British Heart Foundation Centre of Research Excellence, Cardiovascular Division, King's College London, London SE5 9NU, UK. dsoong@staffmail.ed.ac.uk.|MRC Centre for Reproductive Health, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. dsoong@staffmail.ed.ac.uk.
authors.forename: Daniel
authors.initials: D
authors.lastname: Soong
authors.affiliation: British Heart Foundation Centre of Research Excellence, Cardiovascular Division, King's College London, London SE5 9NU, UK. cathy.shanahan@kcl.ac.uk.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
authors.affiliation: British Heart Foundation Centre of Research Excellence, Cardiovascular Division, King's College London, London SE5 9NU, UK. derek.warren@uea.ac.uk.|School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK. derek.warren@uea.ac.uk.
authors.forename: Derek T
authors.initials: DT
authors.lastname: Warren
keywords: Rac1; migratory persistence; prelamin A