Phenotypic switch of vascular smooth muscle cells in COVID‐19: Role of cholesterol, calcium, and phosphate

Figures

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  Figure 1. Potential mechanisms promoting vascular smooth muscle cells (VSMC) calcification and its phenotype switch, resulting in increased severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) replication and entry. Calcification plays an important role in the VSMCs phenotypic switch. On one hand, an increased Ca2+ flow can be mediated through the transient receptor potential vanilloid 4 (TRPV4) on the VSMCs surface, resulting in their dedifferentiation. On the other hand, phenotypic switch can itself promote Ca2+ deposition. This calcification further enhances the SARS‐CoV‐2 replication via the renin‐angiotensin‐aldosterone (RAAS) activation. Moreover, lipid molecules can have a stimulatory effect on calcium, as well as on the coronavirus entry through toll‐like receptor 4 (TLR4) and angiotensin‐converting enzyme 2 (ACE2) receptor enhanced by heparan sulfate proteoglycan (HSPG). In fact, other mechanisms can also stimulate calcium deposits. For instance, ascorbate, O2, Fe2+, and 2‐oxyglutarate result in hyperphosphatemia, which activates the hypoxia‐inducible factor‐1 (HIF‐1), responsible of stimulating the vascular endothelial growth factor (VEGF), an important factor for…

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  Figure 2. Summary of the interplay between vascular smooth muscle cell (VSMC) phenotypic switch, vascular calcification, and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) entry into the cell. Contractile VSMCs can undergo a phenotypic switch under hyperphosphatemia, which results in dedifferentiated VSMCs. This can lead to vascular calcification, which can exert positive feedback on the phenotypic switch. Vascular calcification enhances the SARS‐CoV‐2 entry into the host cell, and can be stimulated by high cholesterol levels. Created with BioRender.com.

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  Figure 3. Mechanism by which 25HC blocks severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) fusion with the vascular smooth muscle cell (VSMC) lipid raft microdomain. 25‐hydroxycholesterol (25HC) inhibits sterol‐regulatory element binding proteins‐2 (SREBP‐2) and activates liver X receptor (LXR), which in turn stimulates acyl‐CoA cholesterol acyltransferase. This results in the depletion of cholesterol, glycosphingolipids, and the glycosylphosphatidylinositol (GPI)‐anchored proteins from the lipid raft microdomain, which then inhibits the entry of the SARS‐CoV‐2 into the host cell. Created with BioRender.com. ACAT, acyl‐CoA cholesterol acyltransferase.

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  Figure 4. The mechanism of inhibiting calcification through chemerin's effect on vascular smooth muscle cells (VSMC). Chemerin, an adipokine found in patients with impaired renal function binds to its receptor on VSMC surface, promoting in the expression of two calcification inhibitors, the fetuin A and matrix Gla protein (MGP). Created with BioRender.com.

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  Figure 5. The effect of various vascular smooth muscle cell (VSMC) phenotypes on the calcification state of the atherosclerotic plaque. Some contractile VSMCs' markers, such as myosin heavy chain (MYH11), smooth muscle aortic alpha‐actin (ACTA2), and smooth muscle 22 alpha (SM22α) are downregulated in atherosclerosis; however, others like runt‐related transcription factor 2 (RUNX2), osteopontin, osteocalcin, type II and X collagen, alkaline phosphatase (ALP), and SRY‐box transcription factor 9 (Sox9) are upregulated. This prompts VSMCs to assume another phenotype. Synthetic VSMCs secrete PS and annexin A6, recruit macrophages to the plaque, and decrease calcification inhibitors like matrix Gla protein (MGP) and fetuin‐A, therefore inducing in calcium deposits. Created with BioRender.com.