Abstract
Mechanical stimulation regulates endothelial cell (EC) functions through the modulation of signaling networks and gene expression. Our recent studies have identified that shear stress regulation of microRNAs (miRs)-19a, 23b and 27b, led to the modulation of EC proliferation. However, the underlying molecular mechanisms by which shear stress regulates these miRs have not been explored. Previous studies showed that shear stress activates multiple signaling pathways, including phosphatidylinositol 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK). In this work we demonstrate that inhibition of the PI3K pathway attenuated the shear-induced miR-19a, and inhibition of the MAPK pathway attenuated miR-23b, 27b. The knockdown of miR-19a using antagomir-19a oligonucleotide (AM19a) decreased the shear-induced PI3K activation; whereas AM-23b, 27b reduced the shear-induced MAPK activation. Furthermore, the overexpression of miR-19a overrode the suppressive effects of PI3K inhibitors on shear-induced PI3K activation; the overexpression of miR-23b, 27b had similar effects on ERK activations, but had little effect on P38 and JNK activation. Our findings suggest a positive feedback loop whereby PI3K and MAPK mediate the shear regulation of miR expression, which in turn modulates the shear-regulated PI3K/MAPK signaling events in ECs.
Highlights
Hemodynamic forces regulate the structure and function of the blood vessel wall, which was reported by Langille et al [1]
Present in the straight portions of the tree, elicits a potential anti-inflammatory and atheroprotective response in endothelial cell (EC) [6]. We focused on this atheroprotective shear stress force and found an upregulation of a distinct group of miRNAs that led to distinct functional consequences [7,8]
Inhibition of phosphatidylinositol 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) Pathways Attenuated the Shear-Induction of miR-19a and miR-23b/27b, Respectively
Summary
Hemodynamic forces regulate the structure and function of the blood vessel wall, which was reported by Langille et al [1]. Vascular endothelial cells (ECs), located at the interface between the circulating blood and the blood vessel, are exposed to shear stresses resulting from the tangential forces exerted by the flowing fluid on the vessel wall, leading to the modulation of signaling networks and expression of microRNAs [2,3,4]. ECs respond to changes of blood flow and distending pressure and convert mechanical stimuli into intracellular signals to affect cellular functions, e.g., proliferation, apoptosis, migration, permeability, and remodeling, as well as gene expression [3,5]. We focused on this atheroprotective shear stress force and found an upregulation of a distinct group of miRNAs that led to distinct functional consequences [7,8]. The mechanisms by which shear stresses regulate miR expression remain unexplored
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