Vascular endothelial cell specification in health and disease
AbstractThere are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling...
Source: Angiogenesis - April 12, 2021 Category: Molecular Biology Source Type: research

Adieu to parting Editor in Chief and pioneering scientist Dr. Joyce Bischoff
(Source: Angiogenesis)
Source: Angiogenesis - April 11, 2021 Category: Molecular Biology Source Type: research

Mechanisms and cell lineages in lymphatic vascular development
AbstractLymphatic vessels have critical roles in both health and disease and their study is a rapidly evolving area of vascular biology. The consensus on how the first lymphatic vessels arise in the developing embryo has recently shifted. Originally, they were thought to solely derive by sprouting from veins. Since then, several studies have uncovered novel cellular mechanisms and a diversity of contributing cell lineages in the formation of organ lymphatic vasculature. Here, we review the key mechanisms and cell lineages contributing to lymphatic development, discuss the advantages and limitations of experimental techniqu...
Source: Angiogenesis - April 6, 2021 Category: Molecular Biology Source Type: research

First blood: the endothelial origins of hematopoietic progenitors
AbstractHematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which...
Source: Angiogenesis - March 30, 2021 Category: Molecular Biology Source Type: research

SMAD6 transduces endothelial cell flow responses required for blood vessel homeostasis
AbstractFluid shear stress provided by blood flow instigates a transition from active blood vessel network expansion during development, to vascular homeostasis and quiescence that is important for mature blood vessel function. Here we show that SMAD6 is required for endothelial cell flow-mediated responses leading to maintenance of vascular homeostasis. Concomitant manipulation of the mechanosensor Notch1 pathway and SMAD6 expression levels revealed that SMAD6 functions downstream of ligand-induced Notch signaling and transcription regulation. Mechanistically, full-length SMAD6 protein was needed to rescue Notch loss-indu...
Source: Angiogenesis - March 29, 2021 Category: Molecular Biology Source Type: research

Depletion of Arg/Abl2 improves endothelial cell adhesion and prevents vascular leak during inflammation
AbstractEndothelial barrier disruption and vascular leak importantly contribute to organ dysfunction and mortality during inflammatory conditions like sepsis and acute respiratory distress syndrome. We identified the kinase Arg/Abl2 as a mediator of endothelial barrier disruption, but the role of Arg in endothelial monolayer regulation and its relevance in vivo remain poorly understood. Here we show that depletion of Arg in endothelial cells results in the activation of both RhoA and Rac1, increased cell spreading and elongation, redistribution of integrin-dependent cell-matrix adhesions to the cell periphery, and improved...
Source: Angiogenesis - March 26, 2021 Category: Molecular Biology Source Type: research

Circulating level of Angiopoietin-2 is associated with acute kidney injury in coronavirus disease 2019 (COVID-19)
(Source: Angiogenesis)
Source: Angiogenesis - March 23, 2021 Category: Molecular Biology Source Type: research

Angiodiversity and organotypic functions of sinusoidal endothelial cells
Abstract‘Angiodiversity’ refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to dis continuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood–brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of disco...
Source: Angiogenesis - March 21, 2021 Category: Molecular Biology Source Type: research

Hydrogel-mediated delivery of microRNA-92a inhibitor polyplex nanoparticles induces localized angiogenesis
AbstractLocalized stimulation of angiogenesis is an attractive strategy to improve the repair of ischemic or injured tissues. Several microRNAs (miRNAs) such as miRNA-92a (miR-92a) have been reported to negatively regulate angiogenesis in ischemic disease. To exploit the clinical potential of miR-92a inhibitors, safe and efficient delivery needs to be established. Here, we used deoxycholic acid-modified polyethylenimine polymeric conjugates (PEI-DA) to deliver a locked nucleic acid (LNA)-based miR-92a inhibitor (LNA-92a) in vitro and in vivo. The positively charged PEI-DA conjugates condense the negatively charged inhibito...
Source: Angiogenesis - March 19, 2021 Category: Molecular Biology Source Type: research

Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression
AbstractFocal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the specific involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. UsingPdgfr βCre + ;FAKWT/WT,Pdgfr βCre + ;FAKY397F/Y397F andPdgfr βCre + ;FA...
Source: Angiogenesis - March 17, 2021 Category: Molecular Biology Source Type: research

The adaptor protein Grb2b is an essential modulator for lympho-venous sprout formation in the zebrafish trunk
AbstractVegfc/Vegfr3 signaling is critical for lymphangiogenesis, the sprouting of lymphatic vessels. In zebrafish, cells sprouting from the posterior cardinal vein can either form lymphatic precursor cells or contribute to intersegmental vein formation. Both, the Vegfc-dependent differential induction of Prox1a in sprouting cells as well as a Notch-mediated pre-pattern within intersegmental vessels have been associated with the regulation of secondary sprout behavior. However, how exactly a differential lymphatic versus venous sprout cell behavior is achieved is not fully understood. Here, we characterize a zebrafish muta...
Source: Angiogenesis - March 7, 2021 Category: Molecular Biology Source Type: research

Endothelial TRPV4 channels prevent tumor growth and metastasis via modulation of tumor angiogenesis and vascular integrity
AbstractTransient receptor potential vanilloid 4 (TRPV4) is a ubiquitously expressed polymodally activated ion channel. TRPV4 has been implicated in tumor progression; however, the cell-specific role of  TRPV4 in tumor growth, angiogenesis, and metastasis is unknown. Here, we generated endothelial-specific TRPV4 knockout (TRPV4ECKO) mice by crossing  TRPV4lox/lox mice with Tie2-Cre mice. Tumor growth and metastasis were significantly increased in a syngeneic Lewis lung carcinoma tumor model of TRPV4ECKO mice compared to TRPV4lox/lox mice. Multiphoton microscopy, dextran leakage, and immunohistochemical ...
Source: Angiogenesis - March 3, 2021 Category: Molecular Biology Source Type: research

Linalool inhibits the angiogenic activity of endothelial cells by downregulating intracellular ATP levels and activating TRPM8
AbstractAngiogenesis crucially contributes to various diseases, such as cancer and diabetic retinopathy. Hence, anti-angiogenic therapy is considered as a powerful strategy against these diseases. Previous studies reported that the acyclic monoterpene linalool exhibits anticancer, anti-inflammatory and anti-oxidative activity. However, the effects of linalool on angiogenesis still remain elusive. Therefore, we investigated the action of (3R)-( −)-linalool, a main enantiomer of linalool, on the angiogenic activity of human dermal microvascular endothelial cells (HDMECs) by a panel of angiogenesis assays. Non-cyto...
Source: Angiogenesis - March 2, 2021 Category: Molecular Biology Source Type: research

Loss of endothelial glucocorticoid receptor promotes angiogenesis via upregulation of Wnt/ β-catenin pathway
ConclusionsLack of endothelial GR triggers autophagy flux, leads to activation of Wnt/ β-catenin signaling and promotes angiogenesis. There may also be a synergistic interaction between autophagy and Wnt/β-catenin signaling. (Source: Angiogenesis)
Source: Angiogenesis - March 2, 2021 Category: Molecular Biology Source Type: research

7-ketocholesterol induces endothelial-mesenchymal transition and promotes fibrosis: implications in neovascular age-related macular degeneration and treatment
AbstractOxidized cholesterols and lipids accumulate in Bruch ’s membrane in age-related macular degeneration (AMD). It remains unknown what causal relationship exists between these substances and AMD pathophysiology. We addressed the hypothesis that a prevalent form, 7-ketocholesterol (7KC), promotes choroidal endothelial cell (CEC) migration and macular ne ovascularization in AMD. Compared to control, 7KC injection caused 40% larger lectin-stained lesions, but 70% larger lesions measured by optical coherence tomography one week after laser-injury. At two weeks, 7KC-injected eyes had 86% larger alpha smooth muscle ac...
Source: Angiogenesis - February 28, 2021 Category: Molecular Biology Source Type: research

Dysbiotic stress increases the sensitivity of the tumor vasculature to radiotherapy and c-Met inhibitors
AbstractAntibiotic-induced microbial imbalance, or dysbiosis, has systemic and long-lasting effects on the host and response to cancer therapies. However, the effects on tumor endothelial cells are largely unknown. Therefore, the goal of the current study was to generate matched B16-F10 melanoma associated endothelial cell lines isolated from mice with and without antibiotic-induced dysbiosis. After validating endothelial cell markers on a genomic and proteomic level, functional angiogenesis assays (i.e., migration and tube formation) also confirmed their vasculature origin. Subsequently, we found that tumor endothelial ce...
Source: Angiogenesis - February 24, 2021 Category: Molecular Biology Source Type: research

Atorvastatin pleiotropically decreases intraplaque angiogenesis and intraplaque haemorrhage by inhibiting ANGPT2 release and VE-Cadherin internalization
ConclusionsAtorvastatin has beneficial effects on vessel remodeling due to its lipid-lowering capacity. Atorvastatin has strong pleiotropic effects on IPA by decreasing the number of neovessels and on IPH by increasing vessel maturation. Atorvastatin improves vessel maturation by inhibiting ANGPT2 release and phospho(Y658)-mediated VE-Cadherin internalization. (Source: Angiogenesis)
Source: Angiogenesis - February 7, 2021 Category: Molecular Biology Source Type: research

Refractory severe idiopathic systemic capillary leak syndrome successfully treated with bevacizumab: a case report
(Source: Angiogenesis)
Source: Angiogenesis - February 7, 2021 Category: Molecular Biology Source Type: research

The DOCK protein family in vascular development and disease
AbstractThe vascular network is established and maintained through the processes of vasculogenesis and angiogenesis, which are tightly regulated during embryonic and postnatal life. The formation of a functional vasculature requires critical cellular mechanisms, such as cell migration, proliferation and adhesion, which are dependent on the activity of small Rho GTPases, controlled in part by the dedicator of cytokinesis (DOCK) protein family. Whilst the majority of DOCK proteins are associated with neuronal development, a growing body of evidence has indicated that members of the DOCK family may have key functions in the c...
Source: Angiogenesis - February 6, 2021 Category: Molecular Biology Source Type: research

RSF1 requires CEBP/ β and hSNF2H to promote IL-1β-mediated angiogenesis: the clinical and therapeutic relevance of RSF1 overexpression and amplification in myxofibrosarcomas
In conclusion, RSF1 overexpression, partly attributable toRSF1 amplification, contributes a novel proangiogenic function by partnering with CEBP/ β to cotransactivateIL1B, highlighting its prognostic, pathogenetic, and therapeutic relevance in myxofibrosarcomas. (Source: Angiogenesis)
Source: Angiogenesis - January 26, 2021 Category: Molecular Biology Source Type: research

A novel lymphatic pattern promotes metastasis of cervical cancer in a hypoxic tumour-associated macrophage-dependent manner
We describe these aggregates as LVEM (LVs encapsulated by TAMs) considering their advantageous metastatic capacity and active involvement in early lymph node metastasis (LNM). Mechanistic investigations revealed that interleukin-10 (IL-10) derived from hypoxic TAMs adjacent to LVs was a prerequisite for lymphangiogenesis and LVEM formation through its induction of Sp1 upregulation in lymphatic endothelial cells (LECs). Interestingly, Sp1high LECs promoted the transactivation of C –C motif chemokine ligand 1 (CCL1) to facilitate TAM and tumour cell recruitment, thereby forming a positive feedback loop to strengthen th...
Source: Angiogenesis - January 23, 2021 Category: Molecular Biology Source Type: research

Human endothelial colony-forming cells provide trophic support for pluripotent stem cell-derived cardiomyocytes via distinctively high expression of neuregulin-1
AbstractThe search for a source of endothelial cells (ECs) with translational therapeutic potential remains crucial in regenerative medicine. Human blood-derived endothelial colony-forming cells (ECFCs) represent a promising source of autologous ECs due to their robust capacity to form vascular networks in vivo and their easy accessibility from peripheral blood. However, whether ECFCs have distinct characteristics with translational value compared to other ECs remains unclear. Here, we show that vascular networks generated with human ECFCs exhibited robust paracrine support for human pluripotent stem cell-derived cardiomyo...
Source: Angiogenesis - January 17, 2021 Category: Molecular Biology Source Type: research

Circulating Von Willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality
AbstractBackgroundCoronavirus disease 2019 (COVID-19) is a respiratory disease associated with endotheliitis and microthrombosis.ObjectivesTo correlate endothelial dysfunction to in-hospital mortality in a bi-centric cohort of COVID-19 adult patients.MethodsConsecutive ambulatory and hospitalized patients with laboratory-confirmed COVID-19 were enrolled. A panel of endothelial biomarkers and von Willebrand factor (VWF) multimers were measured in each patient ≤ 48 h following admission.ResultsStudy enrolled 208 COVID-19 patients of whom 23 were mild outpatients and 189 patients hospitalized after admission. M...
Source: Angiogenesis - January 15, 2021 Category: Molecular Biology Source Type: research

To be or not to be: endothelial cell plasticity in development, repair, and disease
AbstractEndothelial cells display an extraordinary plasticity both during development and throughout adult life. During early development, endothelial cells assume arterial, venous, or lymphatic identity, while selected endothelial cells undergo additional fate changes to become hematopoietic progenitor, cardiac valve, and other cell types. Adult endothelial cells are some of the longest-lived cells in the body and their participation as stable components of the vascular wall is critical for the proper function of both the circulatory and lymphatic systems, yet these cells also display a remarkable capacity to undergo chan...
Source: Angiogenesis - January 15, 2021 Category: Molecular Biology Source Type: research

RIPK3 modulates growth factor receptor expression in endothelial cells to support angiogenesis
AbstractReceptor-interacting protein kinase 3 (RIPK3) is a multifunctional intracellular protein that was first recognized as an important component of the necroptosis programmed cell death pathway. RIPK3 is also highly expressed in non-necroptotic murine embryonic endothelial cells (ECs) during vascular development, indicating its potential contribution to angiogenesis. To test this hypothesis, we generated mice lacking endothelial RIPK3 and found non-lethal embryonic and perinatal angiogenesis defects in multiple vascular beds. Our in vitro data indicate that RIPK3 supports angiogenesis by regulating growth factor recept...
Source: Angiogenesis - January 15, 2021 Category: Molecular Biology Source Type: research

Protection of capillaries may be critical in delaying aging around the eyes and prevention of facial plastic surgery
(Source: Angiogenesis)
Source: Angiogenesis - January 15, 2021 Category: Molecular Biology Source Type: research

YAP promotes ocular neovascularization by modifying PFKFB3-driven endothelial glycolysis
AbstractOcular neovascularization is the leading cause of vision impairment in a variety of ocular diseases, such as age-related macular degeneration and retinopathy of prematurity. Emerging studies have suggested that the yes-associated protein (YAP), a downstream effector of the Hippo pathway, is involved in the pathological angiogenesis, but the mechanism are largely unknown. Here, we demonstrated that hypoxic treatment triggered YAP expression and nuclear translocation in human umbilical vein endothelial cells (HUVECs). YAP acted as a transcriptional co-activator working together with transcriptional enhancer activator...
Source: Angiogenesis - January 5, 2021 Category: Molecular Biology Source Type: research

Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: a proof of concept study
In conclusion, oral itraconazole significantly improved epistaxis in HHT patients. The potential benefit of itraconazole in HHT should be further investigated. (Source: Angiogenesis)
Source: Angiogenesis - November 19, 2020 Category: Molecular Biology Source Type: research

Endothelium-specific deletion of Nox4 delays retinal vascular development and mitigates pathological angiogenesis
AbstractNADPH oxidase 4 (Nox4) is a major isoform of NADPH oxidases playing an important role in many biological processes. Previously we have shown that Nox4 is highly expressed in retinal blood vessels and is upregulated in oxygen-induced retinopathy (OIR). However, the exact role of endothelial Nox4 in retinal angiogenesis remains elusive. Herein, using endothelial cell (EC)-specific Nox4 knockout (Nox4EC −KO) mice, we investigated the impact of endothelial Nox4 deletion on retinal vascular development and pathological angiogenesis during OIR. Our results show that deletion of Nox4 in ECs led to retarded retinal v...
Source: Angiogenesis - November 17, 2020 Category: Molecular Biology Source Type: research

Talin-dependent integrin activation is required for endothelial proliferation and postnatal angiogenesis
AbstractIntegrin activation contributes to key blood cell functions including adhesion, proliferation and migration. An essential step in the cell signaling pathway that activates integrin requires the binding of talin to the β-integrin cytoplasmic tail. Whereas this pathway is understood in platelets in detail, considerably less is known regarding how integrin-mediated adhesion in endothelium contributes to postnatal angiogenesis. We utilized an inducible EC-specific talin1 knock-out mouse (Tln1 EC-KO) and talin1 L325R knock-in mutant (Tln1 L325R) mouse, in which talin selectively lacks the capacity to activate integ...
Source: Angiogenesis - October 28, 2020 Category: Molecular Biology Source Type: research

Microvascular dysfunction in COVID-19: the MYSTIC study
ConclusionsOur data clearly show severe alterations of the microcirculation and the endothelial glycocalyx in patients with COVID-19. Future therapeutic approaches should consider the importance of systemic vascular involvement in COVID-19. (Source: Angiogenesis)
Source: Angiogenesis - October 14, 2020 Category: Molecular Biology Source Type: research

Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of pro-angiogenic factor receptors
AbstractReceptor endocytosis is crucial for integrating extracellular stimuli of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), into the cell via signal transduction. VEGF not only triggers various angiogenic events including endothelial cell (EC) migration, but also induces the expression of negative regulators of angiogenesis, including vasohibin-1 (VASH1). While we have previously reported that VASH1 inhibits angiogenesis in vitro and in vivo, its mode of action on EC behavior remains elusive. Recently VASH1 was shown to have tubulin carboxypeptidase (TCP) activity, mediating the post-trans...
Source: Angiogenesis - October 14, 2020 Category: Molecular Biology Source Type: research

Angiogenesis, hereditary hemorrhagic telangiectasia and COVID-19
AbstractHereditary hemorrhagic telangiectasia (HHT) is a rare autosomal-dominant disease characterized by pathologic angiogenesis that provokes vascular overgrowth. The evidence about the influence of Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in patients with rare diseases is scarce. We aimed to know the prevalence of coronavirus disease 2019 (COVID-19) in HHT patients. The HHT pathogenic angiogenesis and endothelial injury in COVID-19 are discussed using data from RiHHTa (Computerized Registry of Hereditary Hemorrhagic Telangiectasia) registry. RiHHTa is an open, multicenter, prospective, observational registr...
Source: Angiogenesis - October 14, 2020 Category: Molecular Biology Source Type: research

3D analysis of microvasculature in murine liver fibrosis models using synchrotron radiation-based microtomography
AbstractCirrhosis describes the development of excess fibrous tissue around regenerative nodules in response to chronic liver injury and usually leads to irreversible organ damage and end-stage liver disease. During the development of cirrhosis, the formation of collagenous scar tissue is paralleled by a reorganization and remodeling of the hepatic vascular system. To date, macrovascular remodeling in various cirrhosis models has been examined using three-dimensional (3D) imaging modalities, while microvascular changes have been studied mainly by two-dimensional (2D) light microscopic and electron microscopic imaging. Here...
Source: Angiogenesis - October 10, 2020 Category: Molecular Biology Source Type: research

Vessel tech: a high-accuracy pipeline for comprehensive mouse retinal vasculature characterization
AbstractMouse retinal vasculature is a well-recognized and commonly used animal model for angiogenesis and microvascular remodeling. Morphological features of retinal vasculature reflect the vessel ’s biological functions, and are critical in understanding the physiological and pathological process of vascular development and disease. Here we developed a comprehensive software,Vessel Tech, using retinal vasculature images of postnatal mice. This pipeline can automatically process retinal vascular images, reconstruct vessel network with high accuracy and assess global and local vascular characteristics based on the re...
Source: Angiogenesis - October 9, 2020 Category: Molecular Biology Source Type: research

BMP6/TAZ-Hippo signaling modulates angiogenesis and endothelial cell response to VEGF
AbstractThe BMP/TGF β-Smad, Notch and VEGF signaling guides formation of endothelial tip and stalk cells. However, the crosstalk of bone morphogenetic proteins (BMPs) and vascular endothelial growth factor receptor 2 (VEGFR2) signaling has remained largely unknown. We demonstrate that BMP family members regulate VEGFR 2 and Notch signaling, and act via TAZ-Hippo signaling pathway. BMPs were found to be regulated after VEGF gene transfer in C57/Bl6 mice and in a porcine myocardial ischemia model. BMPs 2/4/6 were identified as endothelium-specific targets of VEGF. BMP2 modulated VEGF-mediated endothelial sprouting via D...
Source: Angiogenesis - October 5, 2020 Category: Molecular Biology Source Type: research

Piwi-interacting RNAs (piRNAs) as potential biomarkers and therapeutic targets for cardiovascular diseases
AbstractCardiovascular diseases (CVDs) are the leading causes of death worldwide. Increasing reports demonstrated that non-coding RNAs (ncRNAs) have been crucially involved  in the development of CVDs. Piwi-interacting RNAs (piRNAs) are a novel cluster of small non-coding RNAs with strong uracil bias at the 5′ end and 2′-O-methylation at the 3 ′ end that are mainly present in the mammalian reproductive system and stem cells and serve as potential modulators of developmental and pathophysiological processes. Recently, piRNAs have been reported to be widely expressed in human tissues and can potentiall...
Source: Angiogenesis - October 3, 2020 Category: Molecular Biology Source Type: research

Characterization of a neutralizing anti-human galectin-1 monoclonal antibody with angioregulatory and immunomodulatory activities
AbstractGalectins, a family of highly conserved β-galactoside-binding proteins, control tumor progression by modulating different hallmarks of cancer. Galectin-1 (Gal-1), a proto-type member of this family, plays essential roles in tumor angiogenesis and immunosuppression by cross-linking glycosylated receptors on the surface of endothelial and immune cells. Targeted disruption of Gal-1 suppresses tumor growth by counteracting aberrant angiogenesis and reinforcing antitumor immunity in several experimental settings. Given the multiple therapeutic benefits associated with Gal-1 blockade, several Gal-1 inhibitors, inclu...
Source: Angiogenesis - September 30, 2020 Category: Molecular Biology Source Type: research

AgeR deletion decreases soluble fms-like tyrosine kinase 1 production and improves post-ischemic angiogenesis in uremic mice
AbstractPeripheral arterial disease occurs more frequently and has a worse prognosis in patients with chronic kidney disease (CKD). The receptor for advanced glycation end products (RAGE) is involved in multiple aspects of uremia-associated vasculopathy. Previous data suggest that the RAGE pathway may promote soluble fms-like tyrosine kinase 1 (sFlt1) production, an anti-angiogenic molecule. Thus, we tested the hypothesis that the deletion ofAgeR would decrease sFlt1 production and improve post-ischemic revascularization in uremic condition. We used a well-established CKD model (5/6 nephrectomy) in WT andAgeR−/&minus...
Source: Angiogenesis - September 22, 2020 Category: Molecular Biology Source Type: research

Angiogenic responses in a 3D micro-engineered environment of primary endothelial cells and pericytes
AbstractAngiogenesis plays a key role in the pathology of diseases such as cancer, diabetic retinopathy, and age-related macular degeneration. Understanding the driving forces of endothelial cell migration and organization, as well as the time frame of these processes, can elucidate mechanisms of action of important pathological pathways. Herein, we have developed an organ-specific microfluidic platform recapitulating the in vivo angiogenic microenvironment by co-culturing mouse primary brain endothelial cells with brain pericytes in a three-dimensional (3D) collagen scaffold. As a proof of concept, we show that this model...
Source: Angiogenesis - September 20, 2020 Category: Molecular Biology Source Type: research

A drug-tunable Flt23k gene therapy for controlled intervention in retinal neovascularization
AbstractGene therapies that chronically suppress vascular endothelial growth factor (VEGF) represent a new approach for managing retinal vascular leakage and neovascularization. However, constitutive suppression of VEGF in the eye may have deleterious side effects. Here, we developed a novel strategy to introduce Flt23k, a decoy receptor that binds intracellular VEGF, fused to the destabilizing domain (DD) ofEscherichia coli dihydrofolate reductase (DHFR) into the retina. The expressed DHFR(DD)-Flt23k fusion protein is degraded unless “switched on” by administering a stabilizer; in this case, the antibiotic tri...
Source: Angiogenesis - September 14, 2020 Category: Molecular Biology Source Type: research

RNA m6A methylation promotes the formation of vasculogenic mimicry in hepatocellular carcinoma via Hippo pathway
In conclusion, m6A methylation plays a key role in VM formation in HCC. METTL3 and YAP1 could be potential therapeutic targets via impairing VM formation in anti-metastatic strategies. (Source: Angiogenesis)
Source: Angiogenesis - September 12, 2020 Category: Molecular Biology Source Type: research

Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells
AbstractLymphatic and blood vascular endothelial cells (ECs) share several molecular and developmental features. However, these two cell types possess distinct phenotypic signatures, reflecting their different biological functions. Despite significant advances in elucidating how the specification of lymphatic and blood vascular ECs is regulated at the transcriptional level during development, the key molecular mechanisms governing their lineage identity under physiological or pathological conditions remain poorly understood. To explore the epigenomic signatures in the maintenance of EC lineage specificity, we compared the ...
Source: Angiogenesis - September 11, 2020 Category: Molecular Biology Source Type: research

Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice
AbstractBlood –brain barrier (BBB) dysfunction underlies the pathogenesis of many neurological diseases. Platelet-derived growth factor receptor-alpha (PDGFRα) induces hemorrhagic transformation (HT) downstream of tissue plasminogen activator in thrombolytic therapy of acute stroke. Thus, PDGFs are attractive therapeutic targets for BBB dysfunction. In the present study, we examined the role of PDGF signaling in the process of tissue remodeling after middle cerebral arterial occlusion (MCAO) in mice. Firstly, we found that imatinib increased lesion size after permanent MCAO in wild-type mice. Moreover, i matini...
Source: Angiogenesis - September 11, 2020 Category: Molecular Biology Source Type: research

Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells
In conclusion, our results show that the BMP9-induced aberrant EndMT in PAH pul monary ECs is dependent on exacerbated pro-inflammatory signaling mediated through IL6. (Source: Angiogenesis)
Source: Angiogenesis - August 18, 2020 Category: Molecular Biology Source Type: research

IQGAP1 causes choroidal neovascularization by sustaining VEGFR2-mediated Rac1 activation
AbstractLoss of visual acuity in neovascular age-related macular degeneration (nAMD) occurs when factors activate choroidal endothelial cells (CECs) to transmigrate the retinal pigment epithelium into the sensory retina and develop into choroidal neovascularization (CNV). Active Rac1 (Rac1GTP) is required for CEC migration and is induced by different AMD-related stresses, including vascular endothelial growth factor (VEGF). Besides its role in pathologic events, Rac1 also plays a role in physiologic functions. Therefore, we were interested in a method to inhibit pathologic activation of Rac1. We addressed the hypothesis th...
Source: Angiogenesis - August 10, 2020 Category: Molecular Biology Source Type: research

Leopold Auerbach ’s achievements in the field of vascular system
AbstractThe scientific activity of Leopold Auerbach (1828 –1897) was associated with Wrocław (Brelsau) medical school, which was renowned for brilliant descriptors of cardiovascular system, whose world-famous achievements became eponymous in history of medicine. Such terms as plexus myentericus Auerbach and Friedreich-Auerbach disease are still used wor ldwide. Little is known about the fact that the vascular system was at least as important in his scientific impact as neuromuscular field. Actually, one could realize that ganglion cells, which were previously discovered in cardiac location, were identified by Auerba...
Source: Angiogenesis - July 27, 2020 Category: Molecular Biology Source Type: research

Novel Murine Models of Cerebral Cavernous Malformations
AbstractCerebral cavernous malformations (CCMs) are ectatic capillary-venous malformations that develop in approximately 0.5% of the population. Patients with CCMs may develop headaches, focal neurologic deficits, seizures, and hemorrhages. While symptomatic CCMs, depending upon the anatomic location, can be surgically removed, there is currently no pharmaceutical therapy to treat CCMs. Several mouse models have been developed to better understand CCM pathogenesis and test therapeutics. The most common mouse models induce a large CCM burden that is anatomically restricted to the cerebellum and contributes to lethality in t...
Source: Angiogenesis - July 23, 2020 Category: Molecular Biology Source Type: research

Stromal cell-derived factor 1 (SDF1) attenuates platelet-derived growth factor-B (PDGF-B)-induced vascular remodeling for adipose tissue expansion in obesity
AbstractPlatelet-derived growth factor-B (PDGF-B) is a main factor to promote adipose tissue angiogenesis, which is responsible for the tissue expansion in obesity. In this process, PDGF-B induces the dissociation of pericytes from blood vessels; however, its regulatory mechanism remains unclear. In the present study, we found that stromal cell-derived factor 1 (SDF1) plays an essential role in this regulatory mechanism. SDF1 mRNA was increased in epididymal white adipose tissue (eWAT) of obese mice. Ex vivo pharmacological analyses using cultured adipose tissue demonstrated that physiological concentrations (1 –100&...
Source: Angiogenesis - July 21, 2020 Category: Molecular Biology Source Type: research

Excess centrosomes disrupt vascular lumenization and endothelial cell adherens junctions
AbstractProper blood vessel formation requires coordinated changes in endothelial cell polarity and rearrangement of cell –cell junctions to form a functional lumen. One important regulator of cell polarity is the centrosome, which acts as a microtubule organizing center. Excess centrosomes perturb aspects of endothelial cell polarity linked to migration, but whether centrosome number influences apical–basal polari ty and cell–cell junctions is unknown. Here, we show that excess centrosomes alter the apical–basal polarity of endothelial cells in angiogenic sprouts and disrupt endothelial cell–...
Source: Angiogenesis - July 21, 2020 Category: Molecular Biology Source Type: research