The altered signaling environment in aged tissue produces changes in cell behavior, some of which is adaptive and helpful, and some of which is maladaptive and harmful. In some cases the same process can be one or the other depending on context. Cellular senescence, for example, is helpful in the contexts of cancer suppression and regeneration from injury, but only up until the point at which senescent cells are no longer removed as rapidly as they are created, at which point their continued, unrelenting pro-growth, pro-inflammatory signaling contributes to many of the forms of tissue dysfunction observed in aging.
Vascular smooth muscle is vital to the operation of the vasculature, determining blood pressure via appropriate contraction and dilation of blood vessels in response to environmental cues. Today's open access paper is focused on the ways in which vascular smooth muscle cells change behavior in old tissues. This can change the properties of the smooth muscle, impairing the normal control of blood pressure, but there are also numerous other issues that arise. For example, smooth muscle cells can begin to take on the characteristics of bone cells, and deposit calcium into the vascular wall. This calcification contributes to stiffening of vessels, leading to hypertension and accumulating pressure damage to tissues throughout the body.
Vascular smooth muscle cells (VSMCs) are the most abundant cell in vessels. Earlier experiments have found that VSMCs possess high plasticity. Vascular injury stimulates VSMCs to switch into a dedifferentiated type, also known as synthetic VSMCs, with a high migration and proliferation capacity for repairing vascular injury. In recent years, largely owing to rapid technological advances in single-cell sequencing and cell-lineage tracing techniques, multiple VSMCs phenotypes have been uncovered in vascular aging, atherosclerosis, aortic aneurysm, etc. These VSMCs all down-regulate contractile proteins such as α-SMA and calponin1, and obtain specific markers and similar cellular functions of osteoblast, fibroblast, macrophage, and mesenchymal cells.
The synthetic VSMCs are considered as the de-differentiated state of contractile VSMCs, accompanied by morphologic changes from spindle shape to irregular shape. With the decrease of contractile protein expression, the proliferation and migration ability of synthetic VSMCs was enhanced, which played a role in repairing vascular injury. And true to its name, synthetic VSMCs secrete large amounts of collagen, elastin, and matrix metalloproteinase (MMP) causing vascular extracellular matrix (ECM) remodeling. Therefore, synthetic VSMCs almost exist in all types of vascular diseases such as atherosclerosis, aneurysm, neointima. Synthetic VSMCs are prone to further differentiate into alternative phenotypes such as macrophage-like and osteogenic VSMCs.
Vascular calcification (VC) is a common sign in the aged population and chronic kidney disease (CKD) population, which could consequent in increased artery hardness, impaired elasticity, and deficient compliance in advanced stage. VC can be regarded as a process of osteogenesis since the activation of osteogenic genes in the vascular cells play a pivotal role. Recent studies have gradually pointed out the fact that VSMCs switching to the osteogenic phenotype is the principal reason for vascular calcification. Osteogenic VSMCs are also called osteoblast-like VSMCs because of their similarity to osteoblast.
Macrophage-like VSMCs are termed for their similar surface markers and function with macrophages. Macrophage-like VSMCs demonstrate low expression of contractile markers and possess functions similar to macrophages such as innate immune signaling, phagocytosis, and efferocytosis. The phagocytosis of VSMCs in atherosclerosis relies on its macrophage-like phenotype, so high oxidized LDL and cholesterol are the primary metabolic factors driving macrophage-like VSMCs. However, the proportion of macrophage-like VSMCs in the pathogenesis of atherosclerosis is lower than that of macrophage itself, and the level of the inflammatory factors in macrophage-like VSMCs is also inferior to that of monocyte-derived macrophages. The degree of contribution to pathogenesis is unclear.
The VSMCs that express partial mesenchymal markers are referred to mesenchymal-like VSMCs, but there is no uniform official definition of mesenchymal-like VSMCs. The role of mesenchymal-like VSMCs in arterial disease is uncertain. Earlier studies believed that tunica adventitia derived mesenchymal-like VSMCs contribute to atherosclerotic plaque growth and CKD-induced vascular calcification. Whereas, a recent study found that adventitial VSCs did not differentiate into the pathogenic VSMCs in atherosclerosis. Other work has indicated that mesenchymal-like VSMCs can be induced into macrophage-like VSMCs, or into contractile VSMCs, depending on external stimulus conditions.
Single-cell transcriptome revealed that fibroblast-like VSMCs are present in atherosclerotis plaque. Nevertheless, the markers used to mark fibroblast-like VSMCs and mesenchymal-like VSMCs in single cell sequencing overlapped, creating confusion over their definition. In respect of the gene expression profile displayed by single-cell transcriptome, fibroblast-like VSMCs perform three main functions: synthesizing ECM, enforcing cell-matrix adhesion, and promoting cell proliferation. Fibroblast-like VSMCs switching is associated with arterial fibrosis resulting in increased arterial stiffness.
Great progress has been made in the study of the role of VSMCs phenotype transformation in vascular diseases in the past 20 years. VSMCs phenotype switching provides a new perspective for understanding the pathogenesis of vascular diseases. Importantly, the studies of VSMCs phenotypes provide new ideas and targets for pharmacological treatment. As the master switch that controls VSMCs switch from contractile to all pathogenic phenotypes, KLF4 may be the best therapeutic target. Since a large population of miRNAs has similar roles in regulating the VSMCs phenotype, vesicles with several miRNAs can be attempted to reverse the VSMCs phenotype at the lesion site.
Another future challenge is to accurately manipulate VSMCs phenotype switching to not only prevent vascular disease, but also preserve its function in repairing vascular damage. This depends on a rigorous understanding of the biology of each VSMCs phenotypes and their relationship with vascular diseases. The same phenotypic VSMCs plays distinct roles in different stages of disease, and so it may be a better strategy to firstly induce synthetic VSMCs to proliferate to an appropriate number and then convert it into contractile VSMCs, so that the aorta can obtain both strong contractile ability and thick tunica media.