Prelamin A Accumulation Attenuates Rac1 Activity and Increases the Intrinsic Migrational Persistence of Aged Vascular Smooth Muscle Cells.

Lauren Porter,Catherine Shanahan,Derek Warren,Daniel Soong,Mark Holt

doi:10.3390/cells5040041

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.

Highlights

Ageing is the greatest risk factor in the development of cardiovascular disease yet the mechanisms underlying vessel ageing and how ageing impinges on vascular cell function remain poorly understood [1,2]
immunofluorescence microscopy (IF) revealed that nesprin-2 localised to the nuclear envelope of proliferative Vascular smooth muscle cell (VSMC), in presenescent VSMCs, nesprin-2 was mislocalised from the NE to the endoplasmic reticulum (Figure 1C)
VSMC ageing is driven by prelamin A accumulation and recapitulated the elongated spindle-like morphology displayed by presenescent VSMCs

Summary

Introduction

Ageing is the greatest risk factor in the development of cardiovascular disease yet the mechanisms underlying vessel ageing and how ageing impinges on vascular cell function remain poorly understood [1,2]. Vascular smooth muscle cells (VSMCs) are the major cell type of the arterial wall and normally exist in a contractile, differentiated state to maintain vascular tone. Contractile VSMCs are not terminally differentiated and retain the ability to dedifferentiate to a proliferative, migratory phenotype and enhanced VSMC motility is observed during development, vessel repair and in adverse vessel remodeling associated with restenosis and atherosclerosis [3,4,5]. VSMC phenotypic transition involves dramatic actin remodeling which is regulated by Rho GTPase signalling pathways [6,7]. Recent evidence demonstrates that Rac is essential for VSMC migration and neointimal formation in vivo [8]. Rac signalling is critical for switching between

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Conclusion