BMP-2 Overexpression Augments Vascular Smooth Muscle Cell Motility by Upregulating Myosin Va via Erk Signaling

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.

Negative Fgf8-Bmp2 feed-back is regulated by miR-130 during early cardiac specification

“…These interesting results show Erk1/2 as a regulatory factor in the cardiac induction process. In this sense, previous authors have proposed a similar active role of Bmp in the regulation of FGF/ERK pathway at later stages of cardiovascular development, i.e., during cardiomyocyte differentiation of the anterior heart field (Tirosh-Finkel et al, 2010;Hutson et al, 2010), and during modulation of myosin in vascular smooth muscle cells (Zhang et al, 2014). Taking into account all the above data, we have analyzed the possible influence of some additional factors in order to establish a mechanism which justifies a control pathway of FGF/MAPK from Bmp2 during early cardiac specification.…”

Increased plasma BMP-2 levels are associated with atherosclerosis burden and coronary calcification in type 2 diabetic patients

“…VSMCs represent a significant source of BMP-2, which has been reported to be highly expressed in human vessels [ 34 , 35 ]. Moreover, several studies have consistently shown that BMP-2 enhances VSMC migration [ 36 , 37 ]. Hyperglycemia plays a key role in the regulation of the vascular inflammatory response by activating the recruitment of inflammatory cells to injured arteries.…”

“…Although BMP-2 is important for bone regeneration and is a known mediator of vascular calcification, its role in the regulation of atherosclerotic lesions remains uncertain. BMP-2 exerts proinflammatory, proatherogenic effects and can cause oxidative stress in endothelial cells promoting endothelial cell activation [ 37 ]. The current study demonstrates that plasma levels of BMP-2 are significantly higher in patients with CAD.…”

Angiotensin-(1–7) abrogates angiotensin II-induced proliferation, migration and inflammation in VSMCs through inactivation of ROS-mediated PI3K/Akt and MAPK/ERK signaling pathways

“…After 24 h of incubation, the cells that migrated to the lower surface of the filter were fixed by methanol and stained by 1% crystal violet. The number of stained cells from at least 4 fields for each well was counted using a microscope 55 .…”