New Targets in Atherosclerosis: Vascular Smooth Muscle Cell Plasticity and Macrophage Polarity

Abstract

Purpose: Despite an increase in treatment options, and substantial reductions in cardiovascular mortality over the past half-century, atherosclerosis remains the most prevalent cause of premature mortality worldwide. The development of innovative new therapies is crucial to further minimize atherosclerosis-related deaths. The diverse array of cell phenotypes derived from vascular smooth muscle cells (SMCs) and macrophages within atherosclerotic plaques are increasingly becoming recognized for their beneficial and detrimental roles in plaque stability and disease burden. This review explores how contemporary transcriptomics and fate-mapping studies have revealed vascular cell plasticity as a relatively unexplored target for therapeutic intervention.

Methods: Recent literature for this narrative review was obtained by searching electronic databases (ie, Google Scholar, PubMed). Additional studies were sourced from reference lists and the authors' personal databases.

Findings: The lipid-rich and inflammatory plaque milieu induces SMC phenotypic switching to both beneficial and detrimental phenotypes. Likewise, macrophage heterogeneity increases with disease burden to a variety of pro-inflammatory and anti-inflammatory activation states. These vascular cell phenotypes are determinants of plaque structure stability, and it is therefore highly likely that they influence clinical outcomes. Development of clinical treatments targeting deleterious phenotypes or promoting pro-healing phenotypes remains in its infancy. However, existing treatments (statins) have shown beneficial effects toward macrophage polarization, providing a rationale for more targeted approaches. In contrast, beneficial SMC phenotypic modulation with these pharmacologic agents has yet to be achieved. The range of modulated vascular cell phenotypes provides a multitude of novel targets and the potential to reduce future adverse events.

Implications: Vascular cell phenotypic heterogeneity must continue to be explored to lower cardiovascular events in the future. The rapidly increasing weight of evidence surrounding the role of SMC plasticity and macrophage polarity in plaque vulnerability provides a strong foundation upon which development of new therapeutics must follow. This approach may prove to be crucial in reducing cardiovascular events and improving patient benefit in the future.

Keywords: Atherosclerosis; Macrophage; Single-cell RNA sequencing; Vascular smooth muscle cell.