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.
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.
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.
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.
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.
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.
VEGF induced the translation of a 7‐amino acid peptide (7A) from Hdac7 mRNA in mouse adventitial Sca1+ vascular progenitor cells, which formed a novel MEKK1‐7A‐14‐3‐3γ signal pathway downstream VEGF and contributed to vascular injury repair and neo‐angiogenesis in ischemic tissues. The deficiency of 7A peptide (7A‐null mice) retarded these processes, which could be rescued by exogenous 7A peptide.
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.
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.
Increased CLIC4 expression is an early manifestation and mediator of endothelial dysfunction in pulmonary hypertension.
The salient role of microRNAs in atherogenesis Donaldson, Callum J.; Lao, Ka Hou; Zeng, Lingfang
Journal of molecular and cellular cardiology,
September 2018, 2018-09-00, 20180901, Letnik:
122
Journal Article
Recenzirano
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.
•Haemodynamic flow patterns influence atherogenesis by regulating endothelial miRNAs•Many atherogenic processes are also influenced by non-flow-responsive miRNAs•MiRNAs regulate multiple cell types in all stages of atherosclerotic development•Recent evidences suggest a similar role for lncRNAs in atherosclerosis•MiRNAs offer potentials for prognosis, diagnosis and treatment of atherosclerosis
Circulating levels of asymmetric dimethylarginine (ADMA), a nitric oxide synthase inhibitor, are increased in patients with idiopathic pulmonary hypertension (IPAH). We hypothesized that ADMA ...abrogates gap junctional communication, required for the coordinated regulation of endothelial barrier function and angiogenesis, and so contributes to pulmonary endothelial dysfunction. The effects of ADMA on expression and function of gap junctional proteins were studied in human pulmonary artery endothelial cells; pulmonary endothelial microvascular cells from mice deficient in an enzyme metabolizing ADMA, dimethylarginine dimethylaminohydrolase I (DDAHI); and blood-derived endothelial-like cells from patients with IPAH. Exogenous and endogenous ADMA inhibited protein expression and membrane localization of connexin 43 (Cx43) in a nitric oxide/soluble guanosine monophosphate/c-jun-dependent manner in pulmonary endothelial cells, resulting in the inhibition of gap junctional communication, increased permeability, and decreased angiogenesis. The effects of ADMA were prevented by overexpression of DDAHI or Cx43 and by treatment with rotigaptide. Blood-derived endothelial-like cells from IPAH patients displayed a distinct disease-related phenotype compared to cells from healthy controls, characterized by reduced DDAHI expression, increased ADMA production, and abnormal angiogenesis. In summary, we show that ADMA induces pulmonary endothelial dysfunction via changes in expression and activity of Cx43. Cells from IPAH patients exhibit abnormal DDAHI/Cx43 signaling as well as differences in gap junctional communication, barrier function, and angiogenesis. Strategies that promote DDAHI/Cx43 signaling may have an endothelium-protective effect and be beneficial in pulmonary vascular disease.
Circulating endothelial progenitor cells may be important in the pathogenesis of idiopathic pulmonary arterial hypertension (IPAH) and give rise to endothelial colony-forming cells (ECFCs) in ...culture. These cells represent an accessible surrogate population to investigate endothelial dysfunction in IPAH. Peripheral blood mononuclear cells were cultured from healthy volunteers (n=25, 72% female; age range 23-57 yr) and IPAH patients (n=30, 60% female; age range 22-56 yr). Older IPAH patients (n=6, 50% female; age range 62-82 yr) were also sampled. Distinct colonies appeared after 13-35 days and exhibited a typical cobblestone morphology. The average frequency of colonies and clonal growth of isolated cells was similar in healthy volunteers and IPAH patients. Age-dependent differences were observed however in the number and frequency of colonies, which declines with age in the control but not in IPAH subjects. The endothelial phenotype was confirmed by immunostaining and flow cytometry, exhibiting endothelial and progenitor markers, but not hematopoietic markers. Endothelial cell functions, including proliferation, angiogenesis, migration and responses to apoptotic stimuli, were compared in cells between passages 4 to 7. IPAH cells showed enhanced angiogenic capacity (tube formation on Matrigel), significantly less apoptosis (lower caspase-3/7 activity) in response to serum and growth factor deprivation, and impaired migratory capacity compared with control ECFCs. Dysfunctional transforming growth factor (TGF)-β and bone morphogenetic protein receptor expression and signalling are implicated in IPAH and were assessed by RT-PCR and western blotting. IPAH and control ECFCs differed in their TGF-β type I (ALK5) receptor expression/signalling and in the expression of other regulatory proteins (e.g. chloride-like intracellular channel-4). Blood-derived ECFCs display an endothelial lineage similar to that of mature endothelial cells. ECFCs from IPAH patients have a distinct functional phenotype and exhibit differences in TGF-β receptor superfamily expression/signalling, which may contribute to endothelial dysfunction and vascular remodelling in IPAH.
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