Abstract
Epidemiological studies have demonstrated the importance of cardiovascular diseases in Western countries. Among the cell types associated with a dysfunctional vasculature, smooth muscle (SM) cells are believed to play an essential role in the development of these illnesses. Vascular SM cells are key regulators of the vascular tone and also have an important function in the development of atherosclerosis and restenosis. While in the normal vasculature, contractile SM cells are predominant, in atherosclerotic vascular lesions, synthetic cells migrate toward the neointima, proliferate, and synthetize extracellular matrix proteins. In the present study, we have examined the role of caveolin-3 in the regulation of SM cell phenotype. Caveolin-3 is expressed in vivo in normal arterial SM cells, but its expression appears to be lost in cultured SM cells. Our data show that caveolin-3 expression in the A7r5 SM cell line is associated with increased expression of contractility markers such as SM α-actin, SM myosin heavy chain but decreased expression of the synthetic phenotype markers such as p-Elk and Klf4. Moreover, we also show that caveolin-3 expression can reduce proliferation upon treatment with LDL or PDGF. Finally, we show that caveolin-3-expressing SM cells are less sensitive to apoptosis than control cells upon treatment with oxidized LDL. Taken together, our data suggest that caveolin-3 can regulate the phenotypic switch between contractile and synthetic SM cells. A better understanding of the factors regulating caveolin-3 expression and function in this cell type will permit the development of a better comprehension of the factors regulating SM function in atherosclerosis and restenosis.
Highlights
The development of atherosclerosis is characterized by vascular wall accumulation of lipids, which can attract monocyte-derived macrophages followed by vascular smooth muscle cells
Smooth Muscle Cell Caveolin-3 Expression is Associated with a Switch Toward a Contractile Phenotype Since caveolin-3 protein is lost in cultured cells, we decided to express caveolin-3 in A7r5 cells using the pBABE retrovirus expression vector (Figure 1)
We found that caveolin-3 expression in A7r5 cells (A7r5-Cav3) was associated with a robust increase in the expression levels of contractile protein markers and a reduction in the levels of protein markers of the synthetic phenotype (p-Elk-1, KLF4) compared to control-transduced cells (A7r5-m) (Figure 1A)
Summary
The development of atherosclerosis is characterized by vascular wall accumulation of lipids, which can attract monocyte-derived macrophages followed by vascular smooth muscle cells (vSMC). Migrating and proliferating (i.e., intimal) SM cells have specific properties not normally observed in medial SM cells. These newly acquired properties include the ability of these. Caveolin-3 and vascular smooth muscle cells to produce extracellular matrix proteins and a reduction in the expression of proteins involved in muscle contraction. These cells have been linked to a synthetic phenotype whereas medial SM cells have been associated with a contractile phenotype. Synthetic cells are described with a reduced expression of contractile proteins and an increased expression of proteins involved in migration/invasion and proliferation as well as extracellular matrix protein production. Krüppel-like transcription factor 4 (Klf-4), a known repressor of vSMC contractile marker genes, has been shown to induce a phenotypic switch toward the vSMC synthetic state [8, 12]
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