Abstract
BackgroundBone marrow-derived endothelial progenitor cells (EPCs), especially late EPCs, play a critical role in endothelial maintenance and repair, and postnatal vasculogenesis. Although the actin cytoskeleton has been considered as a modulator that controls the function and modulation of stem cells, its role in the function of EPCs, and in particular late EPCs, remains poorly understood.Methodology/Principal FindingBone marrow-derived late EPCs were treated with jasplakinolide, a compound that stabilizes actin filaments. Cell apoptosis, proliferation, adhesion, migration, tube formation, nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation were subsequently assayed in vitro. Moreover, EPCs were locally infused into freshly balloon-injured carotid arteries, and the reendothelialization capacity was evaluated after 14 days. Jasplakinolide affected the actin distribution of late EPCs in a concentration and time dependent manner, and a moderate concentration of (100 nmol/l) jasplakinolide directly stabilized the actin filament of late EPCs. Actin stabilization by jasplakinolide enhanced the late EPC apoptosis induced by VEGF deprivation, and significantly impaired late EPC proliferation, adhesion, migration and tube formation. Furthermore, jasplakinolide attenuated the reendothelialization capacity of transplanted EPCs in the injured arterial segment in vivo. However, eNOS phosphorylation and NO production were increased in late EPCs treated with jasplakinolide. NO donor sodium nitroprusside (SNP) rescued the functional activities of jasplakinolide-stressed late EPCs while the endothelial NO synthase inhibitor L-NAME led to a further dysfunction induced by jasplakinolide in late EPCs.Conclusions/SignificanceA moderate concentration of jasplakinolide results in an accumulation of actin filaments, enhancing the apoptosis induced by cytokine deprivation, and impairing the proliferation and function of late EPCs both in vitro and in vivo. NO donor reverses these impairments, suggesting the role of NO-related mechanisms in jasplakinolide-induced EPC downregulation. Actin cytoskeleton may thus play a pivotal role in regulating late EPC function.
Highlights
Loss of endothelial integrity and impaired capacity for neovascularization are thought to contribute to cardiovascular diseases, such as atherosclerosis, ischemic events in limbs, retina and myocardium [1,2]
We have demonstrated the biological effects of the stabilization of the actin cytoskeleton by jasplakinolide on late endothelial progenitor cells (EPCs)
The first observation was that jasplakinolide effectively modified the actin cytoskeleton in late EPCs (Fig.2)
Summary
Loss of endothelial integrity and impaired capacity for neovascularization are thought to contribute to cardiovascular diseases, such as atherosclerosis, ischemic events in limbs, retina and myocardium [1,2]. Recent studies have shown that endogenous re-endothelialization and postnatal neovascularization rely on the migration, proliferation and sprouting of preexisting mature endothelial cells, and on the activity of EPCs [3,4]. EPCs possess the capability to interact with the endothelial layer of different organs in a way that causes morphological changes and strong adhesion to the tissue [5]. They promote reendothelialization or stimulate angiogenesis directly by the differentiation into mature endothelial cells and indirectly by their secretary factors that mobilize endothelial and progenitor cells to take part in angiogenesis and reconstruction [6]. The actin cytoskeleton has been considered as a modulator that controls the function and modulation of stem cells, its role in the function of EPCs, and in particular late EPCs, remains poorly understood
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