Role of Vascular Smooth Muscle Cell Plasticity and Interactions in Vessel Wall Inflammation

Abstract

The pathobiology of atherosclerotic disease requires further elucidation to discover new approaches to address its high morbidity and mortality. To date, over 17 million cardiovascular-related deaths have been reported annually, despite a multitude of surgical and nonsurgical interventions and advances in medical therapy. Existing strategies to prevent disease progression mainly focus on management of risk factors, such as hypercholesterolemia. Even with optimum current medical therapy, recurrent cardiovascular events are not uncommon in patients with atherosclerosis, and their incidence can reach 10–15% per year. Although treatments targeting inflammation are under investigation and continue to evolve, clinical breakthroughs are possible only if we deepen our understanding of vessel wall pathobiology. Vascular smooth muscle cells (VSMCs) are one of the most abundant cells in vessel walls and have emerged as key players in disease progression. New technologies, including in situ hybridization proximity ligation assays, in vivo cell fate tracing with the CreERT2-loxP system and single-cell sequencing technology with spatial resolution, broaden our understanding of the complex biology of these intriguing cells. Our knowledge of contractile and synthetic VSMC phenotype switching has expanded to include macrophage-like and even osteoblast-like VSMC phenotypes. An increasing body of data suggests that VSMCs have remarkable plasticity and play a key role in cell-to-cell crosstalk with endothelial cells and immune cells during the complex process of inflammation. These are cells that sense, interact with and influence the behavior of other cellular components of the vessel wall. It is now more obvious that VSMC plasticity and the ability to perform nonprofessional phagocytic functions are key phenomena maintaining the inflammatory state and senescent condition and actively interacting with different immune competent cells.

Role of MicroRNA-145 in DNA Damage Signalling and Senescence in Vascular Smooth Muscle Cells of Type 2 Diabetic Patients

“…Induction and progression of vascular pathophysiological states is multifactorial. Whilst SMC plasticity is central to both adaptive (physiological) and adverse (pathological) remodelling [ 47 ], aging and senescence are singularly detrimental. Importantly, we have identified a novel mechanism linking aberrant miRNA-145 expression to SV-SMC senescence in the setting of macrovascular complications of T2DM.…”

Novel Transcript Discovery Expands the Repertoire of Pathologically-Associated, Long Non-Coding RNAs in Vascular Smooth Muscle Cells

“…Activation of pro-inflammatory cascades likely aids the proliferation of VSMCs, in part through a synergistic potentiation of their response to PDGF-BB [ 39 ]. Additionally, VSMC pro-inflammatory activity is at the core of vessel wall remodelling contexts where a sustained inflammatory response, often from senescent VSMCs, promotes the influx of myeloid cells [ 3 ]. We see clusters of genes associated with cytokine response induced with IL-1α alone or combined IL-1α/PDGF-BB stimulation and a particularly large number of newly assembled lncRNAs were found in these clusters.…”

“…The principal role of vascular smooth muscle cells (VSMCs) in their differentiated state is to provide contractile force in the vessel wall to ensure proper circulation. However, a high level of plasticity relative to other cell types is well established [ 1 , 2 , 3 ], with phenotypes, such as proliferation, migration, and extracellular matrix production, often displayed at the expense of contractility. This adaptability can aid vessel growth and repair in response to a wide range of biochemical signals or mechanical stresses [ 1 ].…”

“…Conversely, it also contributes to vessel wall remodelling during some of the most prevalent and life-threatening cardiovascular diseases, such as atherosclerosis, pulmonary hypertension, and restenosis [ 2 ]. The molecular mechanisms controlling the wide variety of phenotypic changes involved in such diseases are controlled by both coding and non-coding genes at both the genetic and epigenetic level [ 3 , 4 ]. However, they are not yet understood sufficiently to effectively target them therapeutically.…”

ORAI1 Ca2+ Channel as a Therapeutic Target in Pathological Vascular Remodelling

“…These phenotypically modulated VSMCs have reduced expression of contractile proteins, while displaying high indices of proliferation, migration, synthesis and secretion of cytokines and tropoelastins. This phenotypic switch generates a range of de-differentiated VSMC phenotypes, including macrophage-like, osteoblast-like and myofibroblastlike VSMC phenotypes, as reviewed in Sorokin et al (2020). This heterogeneity in VSMC populations within the healthy vessel wall was evident in the heterogeneity of the single VSMCs transcriptional profiles defined by single cell RNA-sequencing (Dobnikar et al, 2018).…”