Mechanisms of vascular smooth muscle cell investment and phenotypic diversification in vascular diseases

Abstract

In contrast with the heart, the adult mammalian vasculature retains significant remodelling capacity, dysregulation of which is implicated in disease development. In particular, vascular smooth muscle cells (VSMCs) play major roles in the pathological vascular remodelling characteristic of atherosclerosis, restenosis, aneurysm and pulmonary arterial hypertension. Clonal lineage tracing revealed that the VSMC-contribution to disease results from the hyperproliferation of few pre-existing medial cells and suggested that VSMC-derived cells from the same clone can adopt diverse phenotypes. Studies harnessing the powerful combination of lineage tracing and single-cell transcriptomics have delineated the substantial diversity of VSMC-derived cells in vascular lesions, which are proposed to have both beneficial and detrimental effects on disease severity. Computational analyses further suggest that the pathway from contractile VSMCs in healthy arteries to phenotypically distinct lesional cells consists of multiple, potentially regulatable, steps. A better understanding of how individual steps are controlled could reveal effective therapeutic strategies to minimise VSMC functions that drive pathology whilst maintaining or enhancing their beneficial roles. Here we review current knowledge of VSMC plasticity and highlight important questions that should be addressed to understand how specific stages of VSMC investment and phenotypic diversification are controlled. Implications for developing therapeutic strategies in pathological vascular remodelling are discussed and we explore how cutting-edge approaches could be used to elucidate the molecular mechanisms underlying VSMC regulation.

Keywords: cardiovascular disease; cell plasticity; lineage tracing; single cell RNA sequencing; vascular smooth muscle.

Figure 1.. Mechanisms that may underlie oligoclonal VSMC lesion contribution.

Mature vascular lesions show contribution from few VSMC clones. Oligoclonality could arise from selective mechanisms at the level of activation of cell proliferation (A) or intimal invasion of expanding VSMC clones (B) or be due to competition for survival (C). Differential success between VSMC clones at each stage could be due to stochastic differences in environmental signals or to cell-intrinsic differences between clones. These mechanisms are not mutually exclusive. IEL: internal elastic lamina, EEL: external elastic lamina.

Figure 2.. Outstanding questions on VSMC phenotypic diversification in atherosclerotic lesions.

Schematic plot illustrating that single-cell RNA-seq (scRNA-seq) technologies have revealed the wide range of transcriptional profiles adopted by VSMC-derived cells in atherosclerotic lesions (A). Trajectory inference analysis suggests a transition from contractile VSMCs to a fibrochondrocytic state via an intermediate SEM (stem cell, endothelial, monocyte) state. However, the exact lineage relationships between VSMC-derived cells of different phenotypes remain to be fully determined, particularly the origin of VSMC-derived macrophage cells. Generation of scRNA-seq datasets requires dissociation of the tissue and thus loss of spatial information. Therefore, the impact of spatial localisation within the plaque on VSMC-derived cell fate transitions remains unknown (B). For example, would it be possible to inhibit the generation of plaque-destabilising phenotypes by inhibiting VSMC-derived cell entry into the lesion core? Moreover, the reversibility of cell transitions and the ability of VSMC-derived cells in the lesion to convert into other states remains unknown (A,C). This is of particular interest in the regressing plaque where alterations in the behaviour and/or fates of VSMC-derived cells are likely to have a significant role in plaque stabilising changes (C).