The Expanding Role of Alternative Splicing in Vascular Smooth Muscle Cell Plasticity

Abstract

Vascular smooth muscle cells (VSMCs) display extraordinary phenotypic plasticity. This allows them to differentiate or dedifferentiate, depending on environmental cues. The ability to 'switch' between a quiescent contractile phenotype to a highly proliferative synthetic state renders VSMCs as primary mediators of vascular repair and remodelling. When their plasticity is pathological, it can lead to cardiovascular diseases such as atherosclerosis and restenosis. Coinciding with significant technological and conceptual innovations in RNA biology, there has been a growing focus on the role of alternative splicing in VSMC gene expression regulation. Herein, we review how alternative splicing and its regulatory factors are involved in generating protein diversity and altering gene expression levels in VSMC plasticity. Moreover, we explore how recent advancements in the development of splicing-modulating therapies may be applied to VSMC-related pathologies.

Keywords: alternative splicing; cardiovascular disease; gene expression; splicing-modulating therapies; vascular smooth muscle cells.

Figure 1

Physiological vascular smooth muscle cell plasticity is vital for vascular repair and homeostasis. At baseline, the tunica media of blood vessels is kept at an appropriate thickness, and vascular smooth muscle cells (VSMCs) have a quiescent, non-migratory contractile phenotype. Following vascular injury, these VSMCs are induced to dedifferentiate to a proliferative, migratory synthetic phenotype. Their growth and increased production of extracellular matrix (ECM) components result in a substantial thickening of the media and formation of a neointima. Followimg vascular repair and reestablishment of homeostasis, synthetic VSMCs are gradually induced to differentiate back to the contractile phenotype.

Figure 2

The main types of alternative mRNA splicing. Precursor mRNA can undergo either constitutive or alternative splicing. Constitutive splicing products (left) lack introns and comprise whole exons in the same sequence as the precursor mRNA (middle). Depending on the type of alternative splicing, different products can be yielded (right). Exon exclusion, and alternative 5′ and 3′ splice site selection result in a truncated transcript. Intron retention produces an elongated transcript, as the intron is not excised. Mutually exclusive exons do not occur together in mature mRNA during splicing and produce separate isoforms.

Figure 3

Examples of key splicing events which regulate vascular smooth muscle cell plasticity. (A) Serine/arginine-rich splicing factor 1 (SRSF1) precursor mRNA undergoes increased intron retention during vascular smooth muscle cell (VSMC) differentiation. This leads to decreased SRSF1 protein expression overall. (B) B-cell lymphoma (Bcl-x) transcripts undergo alternate splice site selection to produce a long (-xL), anti-apoptotic isoform during VSMC dedifferentiation and cell growth. (C) Myocardin (MYOCD) transcripts can switch protein isoforms by excluding or including exon 2a during VSMC dedifferentiation or differentiation.