Abstract
Background. The disruption of physiologic vascular smooth muscle cell (VSMC) migration initiates atherosclerosis development. The biochemical mechanisms leading to dysfunctional VSMC motility remain unknown. Recently, cytokine BMP-2 has been implicated in various vascular physiologic and pathologic processes. However, whether BMP-2 has any effect upon VSMC motility, or by what manner, has never been investigated. Methods. VSMCs were adenovirally transfected to genetically overexpress BMP-2. VSMC motility was detected by modified Boyden chamber assay, confocal time-lapse video assay, and a colony wounding assay. Gene chip array and RT-PCR were employed to identify genes potentially regulated by BMP-2. Western blot and real-time PCR detected the expression of myosin Va and the phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2). Immunofluorescence analysis revealed myosin Va expression locale. Intracellular Ca2+ oscillations were recorded. Results. VSMC migration was augmented in VSMCs overexpressing BMP-2 in a dose-dependent manner. siRNA-mediated knockdown of myosin Va inhibited VSMC motility. Both myosin Va mRNA and protein expression significantly increased after BMP-2 administration and were inhibited by Erk1/2 inhibitor U0126. BMP-2 induced Ca2+ oscillations, generated largely by a “cytosolic oscillator”. Conclusion. BMP-2 significantly increased VSMCs migration and myosin Va expression, via the Erk signaling pathway and intracellular Ca2+ oscillations. We provide additional insight into the pathophysiology of atherosclerosis, and inhibition of BMP-2-induced myosin Va expression may represent a potential therapeutic strategy.
Highlights
Recent studies demonstrate that BMP-2, a cytokine of the transforming growth factor-β superfamily, plays an important role in both physiological and pathophysiological vascular development [1, 2]
Rat vascular smooth muscle cells were primary-cultured via explant method and grown in RPMI1640 supplemented with 10% FBS, 100 μg/mL penicillin, 100 μg/mL streptomycin, and 2 mM L-glutamine at 37∘C in 5% CO2 atmosphere. rVSMCs were utilized for experimentation at passage 4–8 [18]
Single rat VSMC migration traced by time-lapse video microscopy revealed BMP-2 overexpressing VSMCs are faster
Summary
Recent studies demonstrate that BMP-2, a cytokine of the transforming growth factor-β superfamily, plays an important role in both physiological and pathophysiological vascular development [1, 2]. Vascular smooth muscle cells (VSMCs) are a significant source of BMP-2 [4]. The disruption of physiologic vascular smooth muscle cell (VSMC) migration initiates atherosclerosis development. SiRNA-mediated knockdown of myosin Va inhibited VSMC motility. Both myosin Va mRNA and protein expression significantly increased after BMP-2 administration and were inhibited by Erk1/2 inhibitor U0126. BMP-2 significantly increased VSMCs migration and myosin Va expression, via the Erk signaling pathway and intracellular Ca2+ oscillations. We provide additional insight into the pathophysiology of atherosclerosis, and inhibition of BMP-2-induced myosin Va expression may represent a potential therapeutic strategy
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