Showing papers on "Vascular endothelial growth factor B published in 2014"
TL;DR: Silencing of MALAT1 tips the balance from a proliferative to a migratory endothelial cell phenotype in vitro, and its genetic deletion or pharmacological inhibition reduces vascular growth in vivo.
Abstract: Rationale: The human genome harbors a large number of sequences encoding for RNAs that are not translated but control cellular functions by distinct mechanisms. The expression and function of the longer transcripts namely the long noncoding RNAs in the vasculature are largely unknown. Objective: Here, we characterized the expression of long noncoding RNAs in human endothelial cells and elucidated the function of the highly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). Methods and Results: Endothelial cells of different origin express relative high levels of the conserved long noncoding RNAs MALAT1, taurine upregulated gene 1 (TUG1), maternally expressed 3 (MEG3), linc00657, and linc00493. MALAT1 was significantly increased by hypoxia and controls a phenotypic switch in endothelial cells. Silencing of MALAT1 by small interfering RNAs or GapmeRs induced a promigratory response and increased basal sprouting and migration, whereas proliferation of endothelial cells was inhibited. When angiogenesis was further stimulated by vascular endothelial growth factor, MALAT1 small interfering RNAs induced discontinuous sprouts indicative of defective proliferation of stalk cells. In vivo studies confirmed that genetic ablation of MALAT1 inhibited proliferation of endothelial cells and reduced neonatal retina vascularization. Pharmacological inhibition of MALAT1 by GapmeRs reduced blood flow recovery and capillary density after hindlimb ischemia. Gene expression profiling followed by confirmatory quantitative reverse transcriptase-polymerase chain reaction demonstrated that silencing of MALAT1 impaired the expression of various cell cycle regulators. Conclusions: Silencing of MALAT1 tips the balance from a proliferative to a migratory endothelial cell phenotype in vitro, and its genetic deletion or pharmacological inhibition reduces vascular growth in vivo.
797 citations
TL;DR: The functional domains of PECAM-1 and how they contribute to its barrier-enhancing properties are described, as well as various stimuli that initiate PECam-1 signaling and/or function at the endothelial junction and cross-talk of the receptor with other junctional molecules, which can influence endothelial cell function.
Abstract: PECAM-1 (also known as CD31) is a cellular adhesion and signaling receptor comprising six extracellular immunoglobulin (Ig)-like homology domains, a short transmembrane domain and a 118 amino acid cytoplasmic domain that becomes serine and tyrosine phosphorylated upon cellular activation. PECAM-1 expression is restricted to blood and vascular cells. In circulating platelets and leukocytes, PECAM-1 functions largely as an inhibitory receptor that, via regulated sequential phosphorylation of its cytoplasmic domain, limits cellular activation responses. PECAM-1 is also highly expressed at endothelial cell intercellular junctions, where it functions as a mechanosensor, as a regulator of leukocyte trafficking and in the maintenance of endothelial cell junctional integrity. In this review, we will describe (1) the functional domains of PECAM-1 and how they contribute to its barrier-enhancing properties, (2) how the physical properties of PECAM-1 influence its subcellular localization and its ability to influence endothelial cell barrier function, (3) various stimuli that initiate PECAM-1 signaling and/or function at the endothelial junction and (4) cross-talk of PECAM-1 with other junctional molecules, which can influence endothelial cell function.
258 citations
TL;DR: Understanding the regulation of HIF and its influence on inflammatory response offers unique opportunities for drug development to modulate inflammation and ischemia in pathological conditions.
Abstract: Infection, cancer and cardiovascular diseases are the major causes for morbidity and mortality in the United States according to the Center for Disease Control. The underlying etiology that contributes to the severity of these diseases is either hypoxia induced inflammation or inflammation resulting in hypoxia. Therefore, molecular mechanisms that regulate hypoxia-induced adaptive responses in cells are important areas of investigation. Oxygen availability is sensed by molecular switches which regulate synthesis and secretion of growth factors and inflammatory mediators. As a consequence, tissue microenvironment is altered by re-programming metabolic pathways, angiogenesis, vascular permeability, pH homeostasis to facilitate tissue remodeling. Hypoxia inducible factor (HIF) is the central mediator of hypoxic response. HIF regulates several hundred genes and vascular endothelial growth factor (VEGF) is one of the primary target genes. Understanding the regulation of HIF and its influence on inflammatory response offers unique opportunities for drug development to modulate inflammation and ischemia in pathological conditions.
257 citations
TL;DR: The long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides in promoting migration and proliferation of both vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis and vessel remodeling during restenosis after angioplasty are described.
Abstract: Purinergic signaling plays important roles in control of vascular tone and remodeling. There is dual control of vascular tone by ATP released as a cotransmitter with noradrenaline from perivascular sympathetic nerves to cause vasoconstriction via P2X1 receptors, whereas ATP released from endothelial cells in response to changes in blood flow (producing shear stress) or hypoxia acts on P2X and P2Y receptors on endothelial cells to produce nitric oxide and endothelium-derived hyperpolarizing factor, which dilates vessels. ATP is also released from sensory-motor nerves during antidromic reflex activity to produce relaxation of some blood vessels. In this review, we stress the differences in neural and endothelial factors in purinergic control of different blood vessels. The long-term (trophic) actions of purine and pyrimidine nucleosides and nucleotides in promoting migration and proliferation of both vascular smooth muscle and endothelial cells via P1 and P2Y receptors during angiogenesis and vessel remodeling during restenosis after angioplasty are described. The pathophysiology of blood vessels and therapeutic potential of purinergic agents in diseases, including hypertension, atherosclerosis, ischemia, thrombosis and stroke, diabetes, and migraine, is discussed.
256 citations
TL;DR: This review summarizes the current knowledge of mechanosensitive athero-miRs and their role in vascular biology and atherosclerosis and shows that the miR-712/205 family, which is upregulated by disturbed flow, contributes to endothelial inflammation and vascular hyperpermeability by targeting tissue inhibitor of metalloproteinase-3.
Abstract: Atherosclerosis preferentially occurs in arterial regions exposed to disturbed flow, in part, due to alterations in gene expression. MicroRNAs (miRNAs) are small, noncoding genes that post-transcriptionally regulate gene expression by targeting messenger RNA transcripts. Emerging evidence indicates that alteration of flow conditions regulate expression of miRNAs in endothelial cells both in vitro and in vivo. These flow-sensitive miRNAs, known as mechano-miRs, regulate endothelial gene expression and can regulate endothelial dysfunction and atherosclerosis. MiRNAs such as, miR-10a, miR-19a, miR-23b, miR-17-92, miR-21, miR-663, miR-92a, miR-143/145, miR-101, miR-126, miR-712, miR-205, and miR-155, have been identified as mechano-miRs. Many of these miRNAs were initially identified as flow sensitive in vitro and were later found to play a critical role in endothelial function and atherosclerosis in vivo through either gain-of-function or loss-of-function approaches. The key signaling pathways that are targeted by these mechano-miRs include the endothelial cell cycle, inflammation, apoptosis, and nitric oxide signaling. Furthermore, we have recently shown that the miR-712/205 family, which is upregulated by disturbed flow, contributes to endothelial inflammation and vascular hyperpermeability by targeting tissue inhibitor of metalloproteinase-3, which regulates metalloproteinases and a disintegrin and metalloproteinases. The mechano-miRs that are implicated in atherosclerosis are termed as mechanosensitive athero-miRs and are potential therapeutic targets to prevent or treat atherosclerosis. This review summarizes the current knowledge of mechanosensitive athero-miRs and their role in vascular biology and atherosclerosis.
228 citations
Journal Article•
TL;DR: In this article, the authors proposed VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipidtransport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.
Abstract: The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts. Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been proposed to contribute to the pathology of type 2 diabetes. However, few treatment options exist that directly target ectopic lipid accumulation. Recently it was found that vascular endothelial growth factor B (VEGF-B) controls endothelial uptake and transport of fatty acids in heart and skeletal muscle. Here we show that decreased VEGF-B signalling in rodent models of type 2 diabetes restores insulin sensitivity and improves glucose tolerance. Genetic deletion of Vegfb in diabetic db/db mice prevented ectopic lipid deposition, increased muscle glucose uptake and maintained normoglycaemia. Pharmacological inhibition of VEGF-B signalling by antibody administration to db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture, improved β-cell function and ameliorated dyslipidaemia, key elements of type 2 diabetes and the metabolic syndrome. The potential use of VEGF-B neutralization in type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart. Our results demonstrate that the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and type 2 diabetes, and that this barrier can be maintained by inhibition of VEGF-B signalling. We propose VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipid-transport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.
225 citations
TL;DR: It is proposed that endothelial NO represents the key molecule linking cerebrovascular and neuronal function, and this role in the control of central nervous system function is very complex.
Abstract: Endothelial nitric oxide (NO) is generated by constitutively active endothelial nitric oxide synthase (eNOS), an essential enzyme responsible for cardiovascular homeostasis. Historically, endothelial NO was first recognized as a major vasodilator involved in control of vasomotor function and local blood flow. In this review, our attention is focused on the emerging role of endothelial NO in linking cerebrovascular function with cognition. We will discuss the recognized ability of endothelial NO to modulate processing of amyloid precursor protein (APP), influence functional status of microglia, and affect cognitive function. Existing evidence suggests that the loss of NO in cultured human cerebrovascular endothelium causes increased expression of APP and β-site APP-cleaving enzyme 1 (BACE1) thereby resulting in increased secretion of amyloid β peptides (Aβ1-40 and Aβ1-42). Furthermore, increased expression of APP and BACE1 as well as increased production of Aβ peptides was detected in the cerebral microvasculature and brain tissue of eNOS-deficient mice. Since Aβ peptides are considered major cytotoxic molecules responsible for the pathogenesis of Alzheimer's disease, these observations support the concept that a loss of endothelial NO might significantly contribute to the initiation and progression of cognitive decline. In addition, genetic inactivation of eNOS causes activation of microglia and promotes a pro-inflammatory phenotype in the brain. Behavioural analysis revealed that eNOS-deficient mice exhibit impaired cognitive performance thereby indicating that selective loss of endothelial NO has a detrimental effect on the function of neuronal cells. Together with findings from prior studies demonstrating the ability of endothelial NO to affect synaptic plasticity, mitochondrial biogenesis, and function of neuronal progenitor cells, it is becoming apparent that the role of endothelial NO in the control of central nervous system function is very complex. We propose that endothelial NO represents the key molecule linking cerebrovascular and neuronal function.
181 citations
TL;DR: In this paper, the authors investigated the influence of endothelial glycolysis on angiogenesis both in vitro and in vivo by blocking or deleting 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) enzymes.
Abstract: Objective— Vascular cells, particularly endothelial cells, adopt aerobic glycolysis to generate energy to support cellular functions. The effect of endothelial glycolysis on angiogenesis remains unclear. 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) is a critical enzyme for endothelial glycolysis. By blocking or deleting PFKFB3 in endothelial cells, we investigated the influence of endothelial glycolysis on angiogenesis both in vitro and in vivo.
Approach and Results— Under hypoxic conditions or after treatment with angiogenic factors, endothelial PFKFB3 was upregulated both in vitro and in vivo. The knockdown or overexpression of PFKFB3 suppressed or accelerated endothelial proliferation and migration in vitro, respectively. Neonatal mice from a model of oxygen-induced retinopathy showed suppressed neovascular growth in the retina when endothelial PFKFB3 was genetically deleted or when the mice were treated with a PFKFB3 inhibitor. In addition, tumors implanted in mice deficient in endothelial PFKFB3 grew more slowly and were provided with less blood flow. A lower level of phosphorylated protein kinase B was observed in PFKFB3-knockdown endothelial cells, which was accompanied by a decrease in intracellular lactate. The addition of lactate to PFKFB3-knockdown cells rescued the suppression of endothelial proliferation and migration.
Conclusions— The blockade or deletion of endothelial PFKFB3 decreases angiogenesis both in vitro and in vivo. Thus, PFKFB3 is a promising target for the reduction of endothelial glycolysis and its related pathological angiogenesis.
# Significance {#article-title-38}
173 citations
TL;DR: The data indicate that miR-210 is a key factor at the microRNA level in promoting angiogenesis and neurogenesis, which was associated with local increased vascular endothelial growth factor (VEGF) levels, suggesting that mi R-210 may be a potential target for ischemic stroke therapy.
Abstract: Angiogenesis and neurogenesis are crucial processes for brain tissue repair and remodeling after brain injury. Current study shows that microRNA-210 (miR-210) promotes vascular endothelial cell migration and tube formation under hypoxia in vitro. Whether miR-210 overexpression promotes focal angiogenesis and neurogenesis in the normal adult brain is unknown. Adult male C57BL/6 mice (n=54) underwent stereotactic injection of a lentiviral vector carrying miR-210 (LV-miR-210). Following 28 days of miR-210 gene transfer, endothelial cell and neural precursor cell proliferation, microvessel density and downstream angiogenic factor were genotyped. miR-210 was highly expressed in neurons, astrocytes and endothelial cells of the LV-miR-210-injected brain hemisphere. The endothelial cell proliferation and the number of newly formed microvessels were greatly increased in the LV-miR-210-treated mice compared with the controls (P<0.05). Neural progenitor cells in the subventricular zone were greatly increased compared with the controls (P<0.05). The data indicate that miR-210 is a key factor at the microRNA level in promoting angiogenesis and neurogenesis, which was associated with local increased vascular endothelial growth factor (VEGF) levels, suggesting that miR-210 may be a potential target for ischemic stroke therapy.
156 citations
TL;DR: Esm1 is simultaneously a target and modulator of VEGF signaling in endothelial cells, playing a role in angiogenesis, inflammation, and vascular permeability, which might be of potential interest for therapeutic applications.
Abstract: Rationale: Endothelial cell–specific molecule 1 (Esm1) is a secreted protein thought to play a role in angiogenesis and inflammation. However, there is currently no direct in vivo evidence supporting a function of Esm1 in either of these processes. Objective: To determine the role of Esm1 in vivo and the underlying molecular mechanisms. Methods and Results: We generated and analyzed Esm1 knockout ( Esm1 KO ) mice to study its role in angiogenesis and inflammation. Esm1 expression is induced by the vascular endothelial growth factor A (VEGF-A) in endothelial tip cells of the mouse retina. Esm1 KO mice showed delayed vascular outgrowth and reduced filopodia extension, which are both VEGF-A–dependent processes. Impairment of Esm1 function led to a decrease in phosphorylated Erk1/2 (extracellular-signal regulated kinases 1/2) in sprouting vessels. We also found that Esm1 KO mice displayed a 40% decrease in leukocyte transmigration. Moreover, VEGF-induced vascular permeability was decreased by 30% in Esm1 KO mice and specifically on stimulation with VEGF-A 165 but not VEGF-A 121 . Accordingly, cerebral edema attributable to ischemic stroke–induced vascular permeability was reduced by 50% in the absence of Esm1. Mechanistically, we show that Esm1 binds directly to fibronectin and thereby displaces fibronectin-bound VEGF-A 165 leading to increased bioavailability of VEGF-A 165 and subsequently enhanced levels of VEGF-A signaling. Conclusions: Esm1 is simultaneously a target and modulator of VEGF signaling in endothelial cells, playing a role in angiogenesis, inflammation, and vascular permeability, which might be of potential interest for therapeutic applications.
154 citations
TL;DR: Further studies are required to delineate the therapeutic potential of IGF system modulation in pathogenic processes, as in some situations, IGF deficiency appears to contribute to endothelial dysfunction, whereas IGF may be deleterious in others.
Abstract: Endothelial cells line blood vessels and modulate vascular tone, thrombosis, inflammatory responses and new vessel formation. They are implicated in many disease processes including atherosclerosis and cancer. IGFs play a significant role in the physiology of endothelial cells by promoting migration, tube formation and production of the vasodilator nitric oxide. These actions are mediated by the IGF1 and IGF2/mannose 6-phosphate receptors and are modulated by a family of high-affinity IGF binding proteins. IGFs also increase the number and function of endothelial progenitor cells, which may contribute to protection from atherosclerosis. IGFs promote angiogenesis, and dysregulation of the IGF system may contribute to this process in cancer and eye diseases including retinopathy of prematurity and diabetic retinopathy. In some situations, IGF deficiency appears to contribute to endothelial dysfunction, whereas IGF may be deleterious in others. These differences may be due to tissue-specific endothelial cell phenotypes or IGFs having distinct roles in different phases of vascular disease. Further studies are therefore required to delineate the therapeutic potential of IGF system modulation in pathogenic processes.
TL;DR: Recent reports of the multiple functions of VEGF-A signalling during development, organ regeneration and tumour progression are summarized.
Abstract: Angiogenesis, the formation of new networks of blood vessels, has essential roles in embryonic development, organ homeostasis and disease progression. Several signalling molecules, such as vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs), transforming growth factor (TGF)-β and angiopoietin-1 and 2, are known to be key regulators of blood vessel development and network patterning. Among these, the roles of VEGF-A and its receptors in vessel morphogenesis are understood best. VEGF-A signalling plays a crucial role in embryonic development through the regulation of angiogenesis. VEGF-A regulates most of the endothelial response, such as the proliferation and migration of endothelial cells (ECs), vascular permeability and the selection of tip and stalk cells. VEGF-A signalling also regulates organ homeostasis in adults. If an organ is exposed to severe injury, VEGF-A induces the release of paracrine factors from ECs, which increase the rate of regeneration of the organ. VEGF-A signalling also has an important role in the progression of angiogenesis-related diseases, especially cancer. Consequently, many agents that block VEGF-A have been developed and reported as useful tools for the inhibition of the growth and metastatic spread of tumours. Here, we summarize recent reports of the multiple functions of VEGF-A signalling during development, organ regeneration and tumour progression.
TL;DR: The pivotal role of Rac-mediated generation of reactive oxygen species (ROS) to regulate the integrity of endothelium cell-cell junctions and the ability of endothelial adhesion receptors, involved in leukocyte transendothelial migration, to control endothelial permeability to small molecules are discussed.
Abstract: The decrease of endothelial barrier function is central to the long-term inflammatory response. A pathological alteration of the ability of endothelial cells to modulate the passage of cells and solutes across the vessel underlies the development of inflammatory diseases such as atherosclerosis and multiple sclerosis. The inflammatory cytokine tumour necrosis factor (TNF) mediates changes in the barrier properties of the endothelium. TNF activates different Rho GTPases, increases filamentous actin and remodels endothelial cell morphology. However, inhibition of actin-mediated remodelling is insufficient to prevent endothelial barrier disruption in response to TNF, suggesting that additional molecular mechanisms are involved. Here we discuss, first, the pivotal role of Rac-mediated generation of reactive oxygen species (ROS) to regulate the integrity of endothelial cell-cell junctions and, second, the ability of endothelial adhesion receptors such as ICAM-1, VCAM-1 and PECAM-1, involved in leukocyte transendothelial migration, to control endothelial permeability to small molecules, often through ROS generation. These adhesion receptors regulate endothelial barrier function in ways both dependent on and independent of their engagement by immune cells, and orchestrate the crosstalk between leukocyte transendothelial migration and endothelial permeability during inflammation.
TL;DR: VEGF-B has the potential to induce coronary vessel growth and cardiac hypertrophy, which can protect the heart from ischemic damage as well as heart failure and is abundantly expressed in tissues with highly active energy metabolism, where it could support significant metabolic functions.
Abstract: Vascular endothelial growth factor-B (VEGF-B), discovered over 15 years ago, has long been seen as one of the more ambiguous members of the VEGF family. VEGF-B is produced as two isoforms: one that binds strongly to heparan sulfate in the pericellular matrix and a soluble form that can acquire binding via proteolytic processing. Both forms of VEGF-B bind to VEGF-receptor 1 (VEGFR-1) and the neuropilin-1 (NRP-1) coreceptor, which are expressed mainly in blood vascular endothelial cells. VEGF-B-deficient mice and rats are viable without any overt phenotype, and the ability of VEGF-B to induce angiogenesis in most tissues is weak. This has been a puzzle, as the related placenta growth factor (PlGF) binds to the same receptors and induces angiogenesis and arteriogenesis in a variety of tissues. However, it seems that VEGF-B is a vascular growth factor that is more tissue specific and can have trophic and metabolic effects, and its binding to VEGFR-1 shows subtle but important differences compared with that of PlGF. VEGF-B has the potential to induce coronary vessel growth and cardiac hypertrophy, which can protect the heart from ischemic damage as well as heart failure. In addition, VEGF-B is abundantly expressed in tissues with highly active energy metabolism, where it could support significant metabolic functions. VEGF-B also has a role in neuroprotection, but unlike other members of the VEGF family, it does not have a clear role in tumor progression. Here we review what is hitherto known about the functions of this growth factor in physiology and disease.
TL;DR: It is shown that endothelial P GC-1α expression is high in diabetic rodents and humans and that PGC-1 α powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo, and induction of endothelium PGC -1α contributes to multiple aspects of vascular dysfunction in diabetes.
TL;DR: The recent discovery of the endothelium-protective functions of HDL-bound S1P which is chaperoned by apolipoprotein M is discussed, which is important for the modulation of vascular permeability.
Abstract: Sphingosine 1-phosphate (S1P), a lipid mediator produced by sphingolipid metabolism, promotes endothelial cell spreading, vascular maturation/stabilization, and barrier function. S1P is present at high concentrations in the circulatory system, whereas in tissues its levels are low. This so-called vascular S1P gradient is essential for S1P to regulate much physiological and pathophysiological progress such as the modulation of vascular permeability. Cellular sources of S1P in blood has only recently begun to be identified. In this review, we summarize the current understanding of S1P in regulating vascular integrity. In particular, we discuss the recent discovery of the endothelium-protective functions of HDL-bound S1P which is chaperoned by apolipoprotein M.
TL;DR: Endothelial cell–derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.
Abstract: Objective— Cardiovascular disease (CVD), the most common morbidity resulting from atherosclerosis, remains a frequent cause of death. Efforts to develop effective therapeutic strategies have focused on vascular inflammation as a critical pathology driving atherosclerosis progression. Nonetheless, molecular mechanisms underlying this activity remain unclear. Here, we ask whether angiopoietin-like protein 2 (Angptl2), a proinflammatory protein, contributes to vascular inflammation that promotes atherosclerosis progression. Approach and Results— Histological analysis revealed abundant Angptl2 expression in endothelial cells and macrophages infiltrating atheromatous plaques in patients with cardiovascular disease. Angptl2 knockout in apolipoprotein E–deficient mice ( ApoE −/− / Angptl2 −/− ) attenuated atherosclerosis progression by decreasing the number of macrophages infiltrating atheromatous plaques, reducing vascular inflammation. Bone marrow transplantation experiments showed that Angptl2 deficiency in endothelial cells attenuated atherosclerosis development. Conversely, ApoE −/− mice crossed with transgenic mice expressing Angptl2 driven by the Tie2 promoter ( ApoE −/− /Tie2- Angptl2 Tg), which drives Angptl2 expression in endothelial cells but not monocytes/macrophages, showed accelerated plaque formation and vascular inflammation because of increased numbers of infiltrated macrophages in atheromatous plaques. Tie2- Angptl2 Tg mice alone did not develop plaques but exhibited endothelium-dependent vasodilatory dysfunction, likely because of decreased production of endothelial cell–derived nitric oxide. Conversely, Angptl2 −/− mice exhibited less severe endothelial dysfunction than did wild-type mice when fed a high-fat diet. In vitro, Angptl2 activated proinflammatory nuclear factor-κB signaling in endothelial cells and increased monocyte/macrophage chemotaxis. Conclusions— Endothelial cell–derived Angptl2 accelerates vascular inflammation by activating proinflammatory signaling in endothelial cells and increasing macrophage infiltration, leading to endothelial dysfunction and atherosclerosis progression.
TL;DR: A key requirement for cell-autonomous EC FGFR signaling in injury-induced angiogenesis, but not for vascular homeostasis is revealed, identifying the ECFGFR signaling pathway as a target for diseases associated with aberrant vascular proliferation, such as age-related macular degeneration, and for modulating wound healing without the potential toxicity associated with direct manipulation of systemic FGF or VEGF activity.
Abstract: Endothelial cells (ECs) express fibroblast growth factor receptors (FGFRs) and are exquisitely sensitive to FGF signals. However, whether the EC or another vascular cell type requires FGF signaling during development, homeostasis, and response to injury is not known. Here, we show that Flk1-Cre or Tie2-Cre mediated deletion of FGFR1 and FGFR2 (Fgfr1/2Flk1-Cre or Fgfr1/2Tie2-Cre mice), which results in deletion in endothelial and hematopoietic cells, is compatible with normal embryonic development. As adults, Fgfr1/2Flk1-Cre mice maintain normal blood pressure and vascular reactivity and integrity under homeostatic conditions. However, neovascularization after skin or eye injury was significantly impaired in both Fgfr1/2Flk1-Cre and Fgfr1/2Tie2-Cre mice, independent of either hematopoietic cell loss of FGFR1/2 or vascular endothelial growth factor receptor 2 (Vegfr2) haploinsufficiency. Also, impaired neovascularization was associated with delayed cutaneous wound healing. These findings reveal a key requirement for cell-autonomous EC FGFR signaling in injury-induced angiogenesis, but not for vascular homeostasis, identifying the EC FGFR signaling pathway as a target for diseases associated with aberrant vascular proliferation, such as age-related macular degeneration, and for modulating wound healing without the potential toxicity associated with direct manipulation of systemic FGF or VEGF activity.
TL;DR: FoxF1 is required for the formation of embryonic vasculature by regulating endothelial genes critical for vascular development and vascular endothelial growth factor signaling.
Abstract: Rationale:Inactivating mutations in the Forkhead Box transcription factor F1 (FOXF1) gene locus are frequently found in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a lethal congenital disorder, which is characterized by severe abnormalities in the respiratory, cardiovascular, and gastrointestinal systems. In mice, haploinsufficiency of the Foxf1 gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal, and gall bladder morphogenesis. Objective:Although FOXF1 is expressed in multiple mesenchyme-derived cell types, cellular origins and molecular mechanisms of developmental abnormalities in FOXF1-deficient mice and patients with alveolar capillary dysplasia with misalignment of pulmonary veins remain uncharacterized because of lack of mouse models with cell-restricted inactivation of the Foxf1 gene. In the present study, the role of FOXF1 in endothelial cells was examined using a conditional knockout approach. Methods and Results:A novel mous...
TL;DR: The knock-out of sdc-1 abolished several key early signaling events of endothelial cells in response to shear stress including the phosphorylation of Akt, the formation of a spatial gradient in paxillinosphorylation, and the activation of RhoA.
TL;DR: Both pharmacological approaches and potential regenerative therapies hold promise for restoration of impaired endothelial cells in diabetic nephropathy.
Abstract: Endothelial dysfunction has been posited to play an important role in the pathogenesis of diabetic nephropathy (DN). Due to the heterogeneity of endothelial cells (ECs), it is difficult to generalize about endothelial responses to diabetic stimuli. At present, there are limited techniques fordirectly measuring EC function in vivo, so diagnosis of endothelial disorders still largely depends on indirect assessment of mediators arising from EC injury. In the kidney microcirculation, both afferent and efferent arteries, arterioles and glomerular endothelial cells (GEnC) have all been implicated as targets of diabetic injury. Both hyperglycemia per se, as well as the metabolic consequences of glucose dysregulation, are thought to lead to endothelial cell dysfunction. In this regard, endothelial nitric oxide synthase (eNOS) plays a central role in EC dysfunction. Impaired eNOS activity can occur at numerous levels, including enzyme uncoupling, post-translational modifications, internalization and decreased expression. Reduced nitric oxide (NO) bioavailability exacerbates oxidative stress, further promoting endothelial dysfunction and injury. The injured ECs may then function as active signal transducers of metabolic, hemodynamic and inflammatory factors that modify the function and morphology of the vessel wall and interact with adjacent cells, which may activate a cascade of inflammatory and proliferative and profibrotic responses in progressive DN. Both pharmacological approaches and potential regenerative therapies hold promise for restoration of impaired endothelial cells in diabetic nephropathy.
TL;DR: These studies reveal that SMC-MR is necessary for aldosterone-induced vascular remodeling independent of renal effects on blood pressure, and supports exploring MR antagonists and VEGFR1 blockade to prevent pathological vascular remodelling induced by ald testosterone.
Abstract: Objective—Vascular remodeling occurs after endothelial injury, resulting in smooth muscle cell (SMC) proliferation and vascular fibrosis. We previously demonstrated that the blood pressure–regulating hormone aldosterone enhances vascular remodeling in mice at sites of endothelial injury in a placental growth factor–dependent manner. We now test the hypothesis that SMC mineralocorticoid receptors (MRs) directly mediate the remodeling effects of aldosterone and further explore the mechanism. Approach and Results—A wire-induced carotid injury model was performed in wild-type mice and mice with inducible SMC-specific deletion of the MR. Aldosterone did not affect re-endothelialization after injury in wild-type mice. Deletion of SMC-MR prevented the 79% increase in SMC proliferation induced by aldosterone after injury in MR-Intact littermates. Moreover, both injury-induced and aldosterone-enhanced vascular fibrosis were attenuated in SMC-specific MR knockout mice. Further exploration of the mechanism revealed ...
TL;DR: It is concluded that during development, endothelial Acvrl1 plays an essential role to regulate endothelial cell proliferation and arterial identity during angiogenesis, whilst in adult life endothelialAcvrl 1 is required to maintain vascular integrity.
Abstract: Rare inherited cardiovascular diseases are frequently caused by mutations in genes that are essential for the formation and/or function of the cardiovasculature Hereditary Haemorrhagic Telangiectasia is a familial disease of this type The majority of patients carry mutations in either Endoglin (ENG) or ACVRL1 (also known as ALK1) genes, and the disease is characterized by arteriovenous malformations and persistent haemorrhage ENG and ACVRL1 encode receptors for the TGFβ superfamily of ligands, that are essential for angiogenesis in early development but their roles are not fully understood Our goal was to examine the role of Acvrl1 in vascular endothelial cells during vascular development and to determine whether loss of endothelial Acvrl1 leads to arteriovenous malformations Acvrl1 was depleted in endothelial cells either in early postnatal life or in adult mice Using the neonatal retinal plexus to examine angiogenesis, we observed that loss of endothelial Acvrl1 led to venous enlargement, vascular hyperbranching and arteriovenous malformations These phenotypes were associated with loss of arterial Jag1 expression, decreased pSmad1/5/8 activity and increased endothelial cell proliferation We found that Endoglin was markedly down-regulated in Acvrl1-depleted ECs showing endoglin expression to be downstream of Acvrl1 signalling in vivo Endothelial-specific depletion of Acvrl1 in pups also led to pulmonary haemorrhage, but in adult mice resulted in caecal haemorrhage and fatal anaemia We conclude that during development, endothelial Acvrl1 plays an essential role to regulate endothelial cell proliferation and arterial identity during angiogenesis, whilst in adult life endothelial Acvrl1 is required to maintain vascular integrity
TL;DR: Pericyte-specific NG2 ablation causes several structural deficits in blood vessels in intracranial B16F10 melanomas, including decreased pericyte ensheathment of endothelial cells, diminished formation of endothelium junctions, and reduced assembly of the vascular basal lamina.
Abstract: The NG2 proteoglycan stimulates the proliferation and migration of various immature cell types, including pericytes. However, the role of NG2 in mediating pericyte/endothelial cell interaction has been less clear. In this study, we show that pericyte-specific NG2 ablation causes several structural deficits in blood vessels in intracranial B16F10 melanomas, including decreased pericyte ensheathment of endothelial cells, diminished formation of endothelial junctions, and reduced assembly of the vascular basal lamina. These deficits result in decreased tumor vessel patency, increased vessel leakiness, and increased intratumoral hypoxia. NG2-dependent mechanisms of pericyte interaction with endothelial cells are further explored in pericyte/endothelial cell co-cultures. siRNA-mediated NG2 knockdown in pericytes leads to reduced formation of pericyte/endothelial networks, reduced formation of ZO-1 positive endothelial cell junctions, and increased permeability of endothelial cell monolayers. We also show that NG2 knockdown results in loss of β1 integrin activation in endothelial cells, revealing a mechanism for NG2-dependent cross talk between pericytes and endothelial cells.
TL;DR: Endothelial cell stiffness is identified as an important regulator of endothelial surface heterogeneity and of ICAM-1 function, which in turn controls the adhesion and transmigration of neutrophils.
Abstract: Chronic vascular inflammation is driven by interactions between activated leukocytes and the endothelium. Leukocyte β2-integrins bind to endothelial intercellular adhesion molecule 1 (ICAM-1), which allows leukocyte spreading, crawling and transendothelial migration. Leukocytes scan the vascular endothelium for permissive sites to transmigrate, which suggests that there is apical membrane heterogeneity within the endothelium. However, the molecular basis for this heterogeneity is unknown. Leukocyte adhesion induces ICAM-1 clustering, which promotes its association to the actin-binding proteins filamin B, α-actinin-4 and cortactin. We show that these endothelial proteins differentially control adhesion, spreading and transmigration of neutrophils. Loss of filamin B, α-actinin-4 and cortactin revealed adaptor-specific effects on a nuclear-to-peripheral gradient of endothelial cell stiffness. By contrast, increasing endothelial cell stiffness stimulates ICAM-1 function. We identify endothelial α-actinin-4 as a key regulator of endothelial cell stiffness and of ICAM-1-mediated neutrophil transmigration. Finally, we found that the endothelial lining of human and murine atherosclerotic plaques shows elevated levels of α-actinin-4. These results identify endothelial cell stiffness as an important regulator of endothelial surface heterogeneity and of ICAM-1 function, which in turn controls the adhesion and transmigration of neutrophils.
TL;DR: EnNaC is discussed as an aldosterone-regulated plasma membrane protein of the vascular endothelium that could significantly contribute to maintaining of an appropriate arterial blood pressure but, if overexpressed, could participate in the pathogenesis of arterial hypertension.
Abstract: Once upon a time, the expression of the epithelial sodium channel (ENaC) was mainly assigned to the kidneys, colon and sweat glands where it was considered to be the main determinant of sodium homeostasis. Recent, though indirect, evidence for the possible existence of ENaC in a non-epithelial tissue was derived from the observation that the vascular endothelium is a target for aldosterone. Inhibitory actions of the intracellular aldosterone receptors by spironolactone and, more directly, by ENaC blockers such as amiloride supported this view. Shortly after, direct data on the expression of ENaC in vascular endothelium could be demonstrated. There, endothelial ENaC (EnNaC) could be defined as a major regulator of cellular mechanics which is a critical parameter in differentiating between vascular function and dysfunction. Foremost, the mechanical stiffness of the endothelial cell cortex, a layer 50–200 nm beneath the plasma membrane, has been shown to play a crucial role as it controls the production of the endothelium-derived vasodilator nitric oxide (NO) which directly affects the tone of the vascular smooth muscle cells. In contrast to soft endothelial cells, stiff endothelial cells release reduced amounts of NO, the hallmark of endothelial dysfunction. Thus, the combination of endothelial stiffness and myogenic tone might increase the peripheral vascular resistance. An elevation of arterial blood pressure is supposed to be the consequence of such functional changes. In this review, EnNaC is discussed as an aldosterone-regulated plasma membrane protein of the vascular endothelium that could significantly contribute to maintaining of an appropriate arterial blood pressure but, if overexpressed, could participate in the pathogenesis of arterial hypertension.
TL;DR: PTP1b is a key regulator of endothelial VEGFR2 signaling and plays an important role in regulation of the extent of vascular tree formation.
Abstract: Background—Regulation of vascular endothelial growth factor receptor-2 (VEGFR2) signaling is a control point that determines the extent of vascular tree formation. Recent studies demonstrated an important role played by VEGFR2 endothelial trafficking in control of its activity and suggested the involvement of a phosphotyrosine phosphatase 1b (PTP1b) in this process. This study was designed to define the role of PTP1b in endothelial VEGFR2 signaling and its role in regulation of angiogenesis and arteriogenesis. Methods and Results—We generated mice carrying an endothelial-specific deletion of PTP1b and examined the effect of this knockout on VEGF signaling, angiogenesis, and arteriogenesis in vitro and in vivo. PTP1b knockout endothelial cells had increased VEGF-dependent activation of extracellular signal-regulated kinase signaling, sprouting, migration, and proliferation compared with controls. Endothelial PTP1b null mice had increased retinal and Matrigel implant angiogenesis and accelerated wound heali...
TL;DR: It is demonstrated that in vitro culture of early passage human cord blood EPDCs under specific conditions can induce phenotypic changes towards BBB or arterial phenotypes, indicating that these E PDCs maintain enough plasticity to acquire characteristics of a variety of specialized phenotypes.
Abstract: Objective
The vascular system is adapted to specific functions in different tissues and organs. Vascular endothelial cells are important elements of this adaptation, leading to the concept of ‘specialized endothelial cells’. The phenotype of these cells is highly dependent on their specific microenvironment and when isolated and cultured, they lose their specific features after few passages, making models using such cells poorly predictive and irreproducible. We propose a new source of specialized endothelial cells based on cord blood circulating endothelial progenitors (EPCs). As prototype examples, we evaluated the capacity of EPCs to acquire properties characteristic of cerebral microvascular endothelial cells (blood-brain barrier (BBB)) or of arterial endothelial cells, in specific inducing culture conditions.
TL;DR: It is concluded that sufficient vitamin D levels and proper VDR expression are fundamental for angiogenic and oxidative defense function in endothelial cells.
TL;DR: In this paper, the authors showed that vascular endothelial growth factor (VEGF) induced the expression of endothelial markers in breast cancer stem like cells (BCSLCs), and the VEGF-treated BCSLCs formed capillary structure in matrigel and released vWF upon histamine treatment.
Abstract: Recent studies suggested that cancer stem cells (CSCs) are capable of differentiating into endothelial cells and tumor endothelium may be derived from CSCs. But the mechanism remains unclear. We showed that vascular endothelial growth factor (VEGF) induced the expression of endothelial markers in breast cancer stem like cells (BCSLCs). In addition, the VEGF-treated BCSLCs formed capillary structure in matrigel and released vWF upon histamine treatment. The miR-27a expression was significantly increased in VEGF-treated BCSLCs. Antagonizing miR-27a by miR-27a anti-sense oligos (ASOs) in VEGF-treated BCSLCs led to decreased endothelial markers and function, while increasing miR-27a in BCSLCs resulted in enhanced endothelial properties. VEGF enhanced the transcription of miR-27a by increasing RUNX1 binding to miR-27a promoter. Increased miR-27a paralleled the reduced expression of ZBTB10, a known miR-27a target. Both expression of miR-27a and knockdown of ZBTB10 in BCSLCs promoted in vivo angiogenesis and tumor metastasis. Further, we demonstrated that VEGF-treated BCSLCs secreted more endogenous VEGF compared with undifferentiated BCSLCs. Thus, miR-27a promotes angiogenesis by mediating endothelial differentiation of BCSLCs and it may be a new target for anti-angiogenesis cancer therapy.