A histone deacetylase 7-derived peptide promotes vascular regeneration via facilitating 14-3-3γ phosphorylation.

Histone deacetylase 7 (HDAC7) plays a pivotal role in the maintenance of the endothelium integrity. In this study, we demonstrated that the intron-containing Hdac7 mRNA existed in the cytosol and that ribosomes bound to a short open reading frame (sORF) within the 5'-terminal noncoding area of this Hdac7 mRNA in response to vascular endothelial growth factor (VEGF) stimulation in the isolated stem cell antigen-1 positive (Sca1+ ) vascular progenitor cells (VPCs). A 7-amino acid (7A) peptide has been demonstrated to be translated from the sORF in Sca1+ -VPCs in vitro and in vivo. The 7A peptide was shown to receive phosphate group from the activated mitogen-activated protein kinase MEKK1 and transfer it to 14-3-3 gamma protein, forming an MEKK1-7A-14-3-3γ signal pathway downstream VEGF. The exogenous synthetic 7A peptide could increase Sca1+ -VPCs cell migration, re-endothelialization in the femoral artery injury, and angiogenesis in hind limb ischemia. A Hd7-7sFLAG transgenic mice line was generated as the loss-of-function model, in which the 7A peptide was replaced by a FLAG-tagged scrabbled peptide. Loss of the endogenous 7A impaired Sca1+ -VPCs cell migration, re-endothelialization of the injured femoral artery, and angiogenesis in ischemic tissues, which could be partially rescued by the addition of the exogenous 7A/7Ap peptide. This study provides evidence that sORFs can be alternatively translated and the derived peptides may play an important role in physiological processes including vascular remodeling.

The salient role of microRNAs in atherogenesis.

Atherosclerosis, a chronic inflammatory condition that is characterized by the accumulation of lipid-loaded macrophages, occurs preferentially at the arterial branching points where disturbed flow is prominent. The pathogenesis of atherosclerotic lesion formation is a multistage process involving multiple cell types, inflammatory mediators and hemodynamic forces in the vessel wall in response to atherogenic stimuli. Researches from the past decade have uncovered the critical roles of microRNAs (miRNAs) in regulating multiple pathophysiological effects and signaling pathways in endothelial cells (ECs), vascular smooth muscle cells (VSMCs), macrophages and lipid homeostasis, which are key in atherosclerotic lesion formation. The expression of these miRNAs are either in response to biomechanical (flow-responsive) or biochemical (non-flow-responsive) stimuli. Recent evidences also indicate an important role for long non-coding RNAs (lncRNAs) in mediating several atherosclerotic processes. In this review, we provide a detailed summary on the current paradigms in miRNA-dependent regulation, the emerging role of lncRNAs in the initiation and progression of atherosclerosis, and clinical interventions targeting these in an attempt to develop novel diagnostics and treatments for atherosclerosis.

XBP1 splicing triggers miR-150 transfer from smooth muscle cells to endothelial cells via extracellular vesicles.

The interaction between endothelial cells (ECs) and smooth muscle cells (SMCs) plays a critical role in the maintenance of vessel wall homeostasis. The X-box binding protein 1 (XBP1) plays an important role in EC and SMC cellular functions. However, whether XBP1 is involved in EC-SMC interaction remains unclear. In this study, In vivo experiments with hindlimb ischemia models revealed that XBP1 deficiency in SMCs significantly attenuated angiogenesis in ischemic tissues, therefore retarded the foot blood perfusion recovery. In vitro studies indicated that either overexpression of the spliced XBP1 or treatment with platelet derived growth factor-BB up-regulated miR-150 expression and secretion via extracellular vesicles (EVs). The XBP1 splicing-mediated up-regulation of miR-150 might be due to increased stability. The SMC-derived EVs could trigger EC migration, which was abolished by miR-150 knockdown in SMCs, suggesting miR-150 is responsible for SMC-stimulated EC migration. The SMC-derived miR-150-containing EVs or premiR-150 transfection increased vascular endothelial growth factor (VEGF)-A mRNA and secretion in ECs. Both inhibitors SU5416 and LY294002 attenuated EVs-induced EC migration. This study demonstrates that XBP1 splicing in SMCs can control EC migration via SMC derived EVs-mediated miR-150 transfer and miR-150-driven VEGF-A/VEGFR/PI3K/Akt pathway activation, thereby modulating the maintenance of vessel wall homeostasis.

Endothelial and smooth muscle cell transformation in atherosclerosis.

PURPOSE OF REVIEW: Physiologically, endothelial integrity and smooth muscle homeostasis play key roles in the maintenance of vascular structure and functions. Under pathological conditions, endothelial and smooth muscle cells display great plasticity by transdifferentiating into other cell phenotypes. This review aims to update the progress in endothelial and smooth muscle cell transformation and to discuss their underlying mechanisms. RECENT FINDINGS: At the early stage of atherosclerosis, it was traditionally believed that smooth muscle cells from the media migrate into the intima in which they proliferate to form neointimal lesions. Recently, endothelial cells were shown to undergo transformation to form smooth muscle-like cells that contribute to neointimal formation. Furthermore, not only can medial smooth muscle cells migrate and proliferate, they also have the ability to differentiate into macrophages in the intima in which they form foam cells by uptaking lipids. Finally, the discovery of stem/progenitor cells in the vessel wall that can differentiate into all types of vascular cells has complicated the research field even further. SUMMARY: Based on the current progress in the research field, it is worthy to explore the contributions of cell transformation to the pathogenesis of atherosclerosis to understand the mechanisms on how they are regulated in order to develop novel therapeutic application targeting these processes to reverse the disease progression.

Role of biomechanical forces in stem cell vascular lineage differentiation.

Mechanical forces have long been known to play a role in the maintenance of vascular homeostasis in the mature animal and in developmental regulation in the fetus. More recently, it has been shown that stem cells play a role in vascular repair and remodeling in response to biomechanical stress. Laminar shear stress can directly activate growth factor receptors on stem/progenitor cells, initiating signaling pathways leading toward endothelial cell differentiation. Cyclic strain can stimulate stem cell differentiation toward smooth muscle lineages through different mechanisms. In vivo, blood flow in the coronary artery is significantly altered after stenting, leading to changes in biomechanical forces on the vessel wall. This disruption may activate stem cell differentiation into a variety of cells and cause delayed re-endothelialization. Based on progress in the research field, the present review aims to explore the role of mechanical forces in stem cell differentiation both in vivo and in vitro and to examine what this means for the application of stem cells in the clinic, in tissue engineering, and for the management of aberrant stem cell contribution to disease.

Aberrant chloride intracellular channel 4 expression contributes to endothelial dysfunction in pulmonary arterial hypertension.

BACKGROUND: Chloride intracellular channel 4 (CLIC4) is highly expressed in the endothelium of remodeled pulmonary vessels and plexiform lesions of patients with pulmonary arterial hypertension. CLIC4 regulates vasculogenesis through endothelial tube formation. Aberrant CLIC4 expression may contribute to the vascular pathology of pulmonary arterial hypertension. METHODS AND RESULTS: CLIC4 protein expression was increased in plasma and blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension and in the pulmonary vascular endothelium of 3 rat models of pulmonary hypertension. CLIC4 gene deletion markedly attenuated the development of chronic hypoxia-induced pulmonary hypertension in mice. Adenoviral overexpression of CLIC4 in cultured human pulmonary artery endothelial cells compromised pulmonary endothelial barrier function and enhanced their survival and angiogenic capacity, whereas CLIC4 shRNA had an inhibitory effect. Similarly, inhibition of CLIC4 expression in blood-derived endothelial cells from patients with idiopathic pulmonary arterial hypertension attenuated the abnormal angiogenic behavior that characterizes these cells. The mechanism of CLIC4 effects involves p65-mediated activation of nuclear factor-κB, followed by stabilization of hypoxia-inducible factor-1α and increased downstream production of vascular endothelial growth factor and endothelin-1. CONCLUSION: Increased CLIC4 expression is an early manifestation and mediator of endothelial dysfunction in pulmonary hypertension.