LPA4 regulates blood and lymphatic vessel formation during mouse embryogenesis

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 5060-5070 ◽  
Author(s):  
Hayakazu Sumida ◽  
Kyoko Noguchi ◽  
Yasuyuki Kihara ◽  
Manabu Abe ◽  
Keisuke Yanagida ◽  
...  
Keyword(s):  
Critical Role ◽  
Lymphatic Vessels ◽  
Physiological Role ◽  
Lipid Mediator ◽  
Mural Cell ◽  
Mouse Embryogenesis ◽  
Mural Cells ◽  
Adult Mice ◽  
Cell Coverage ◽  
And Function

Abstract Lysophosphatidic acid (LPA) is a potent lipid mediator with a wide variety of biological actions mediated through G protein-coupled receptors (LPA1-6). LPA4 has been identified as a G13 protein-coupled receptor, but its physiological role is unknown. Here we show that a subset of LPA4-deficient embryos did not survive gestation and displayed hemorrhages and/or edema in many organs at multiple embryonic stages. The blood vessels of bleeding LPA4-deficient embryos were often dilated. The recruitment of mural cells, namely smooth muscle cells and pericytes, was impaired. Consistently, Matrigel plug assays showed decreased mural cell coverage of endothelial cells in the neovessels of LPA4-deficient adult mice. In situ hybridization detected Lpa4 mRNA in the endothelium of some vasculatures. Similarly, the lymphatic vessels of edematous embryos were dilated. These results suggest that LPA4 regulates establishment of the structure and function of blood and lymphatic vessels during mouse embryogenesis. Considering the critical role of autotaxin (an enzyme involved in LPA production) and Gα13 in vascular development, we suggest that LPA4 provides a link between these 2 molecules.

scholarly journals Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor

2004 ◽  
Vol 167 (2) ◽  
pp. 293-302 ◽  
Author(s):  
Fubito Nakatsu ◽  
Motohiro Okada ◽  
Fumiaki Mori ◽  
Noriko Kumazawa ◽  
Hiroto Iwasa ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Neuronal Excitability ◽  
Critical Role ◽  
Physiological Role ◽  
Adaptor Protein ◽  
Epileptic Seizures ◽  
Gaba Release ◽  
Long Term Potentiation ◽  
Clathrin Adaptor ◽  
And Function

AP-3 is a member of the adaptor protein (AP) complex family that regulates the vesicular transport of cargo proteins in the secretory and endocytic pathways. There are two isoforms of AP-3: the ubiquitously expressed AP-3A and the neuron-specific AP-3B. Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved. To address this question, we generated mice lacking μ3B, a subunit of AP-3B. μ3B−/− mice suffered from spontaneous epileptic seizures. Morphological abnormalities were observed at synapses in these mice. Biochemical studies demonstrated the impairment of γ-aminobutyric acid (GABA) release because of, at least in part, the reduction of vesicular GABA transporter in μ3B−/− mice. This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway. Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles. This work adds a new aspect to the pathogenesis of epilepsy.

scholarly journals Normal Lymphatic Development and Function in Mice Deficient for the Lymphatic Hyaluronan Receptor LYVE-1

2006 ◽  
Vol 27 (2) ◽  
pp. 595-604 ◽  
Author(s):  
Nicholas W. Gale ◽  
Remko Prevo ◽  
Jorge Espinosa ◽  
David J. Ferguson ◽  
Melissa G. Dominguez ◽  
...  
Keyword(s):  
Lymphatic Vessels ◽  
Physiological Role ◽  
Normal Growth ◽  
Skin Inflammation ◽  
Lewis Lung ◽  
Lymphatic Development ◽  
Lymph Node Sinus ◽  
And Function ◽  
Draining Lymph Nodes ◽  
Hyaluronan Receptor

ABSTRACT The hyaluronan receptor LYVE-1 is expressed abundantly on the surfaces of lymphatic vessels and lymph node sinus endothelial cells from early development, where it has been suggested to function both in cell adhesion/transmigration and as a scavenger for hyaluronan turnover. To investigate the physiological role(s) of LYVE-1, we generated mice in which the gene for the receptor was inactivated by replacement with a β-galactosidase reporter. LYVE-1−/− mice displayed an apparently normal phenotype, with no obvious alteration in lymphatic vessel ultrastructure or function and no apparent change in secondary lymphoid tissue structure or cellularity. In addition, the levels of hyaluronan in tissue and blood were unchanged. LYVE-1−/− mice also displayed normal trafficking of cutaneous CD11c+ dendritic cells to draining lymph nodes via afferent lymphatics and normal resolution of oxazolone-induced skin inflammation. Finally, LYVE-1−/− mice supported normal growth of transplanted B16F10 melanomas and Lewis lung carcinomas. These results indicate that LYVE-1 is not obligatory for normal lymphatic development and function and suggest either the existence of compensatory receptors or a role more specific than that previously envisaged.

Abstract TMP111: Thalidomide and Lenalidomide Treatment Reduces Microhemorrhage in Brain Arteriovenous Malformation in Mice Through Increasing Mural Cell Coverage

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Wan Zhu ◽  
Dingquan Zou ◽  
Wanqiu Chen ◽  
Chen Bao ◽  
Rui Zhang ◽  
...  
Keyword(s):  
Vessel Wall ◽  
Mural Cell ◽  
Mural Cells ◽  
Cell Coverage ◽  
Therapeutic Value ◽  
Vessel Count ◽  
Pdgfr Beta ◽  
Brain Avms ◽  
Thalidomide Treatment ◽  
Deficient Mice

Introduction: Brain arteriovenous malformations (bAVMs) have an abnormal vessel wall and are prone to rupture. The mechanism of bAVM rupture is unclear. In Alk1 -deficient mice, bAVM vessels have fewer mural cells. In endoglin-deficient mice, thalidomide increases mural cells in retina AVM vessels. We hypothesize that thalidomide and its less toxic analogue, lenalidomide, improve vessel mural cell coverage and reduce microhemorrhage in Alk1 -deficient bAVM. Methods: Brain AVMs were induced in adult Alk1 2f/2f mice through induction of focal Alk1 gene deletion and angiogenic stimulation. Thalidomide was injected intraperitoneally (i.p.) twice per week for six weeks, starting either 2 weeks after model induction when bAVMs were beginning to develop or 8 weeks after when bAVMs were fully developed. Lenalidomide treatment was started 8 weeks after model induction through i.p. injection daily for six weeks. Results: Thalidomide treatment starting 2 weeks after bAVM induction reduced the number of abnormal vessels and microhemorrhage and increased vascular smooth muscle (vSM)-coverage. Thalidomide also increased the expression of platelet-derived growth factor b (pdgfb) and its receptor (pdgfr beta), indicating that pdgfg/pdgfr beta signaling is one of the mechanisms responsible for the improvement of mural cell coverage. Thalidomide and lenalidomide treatment started at the later time point also improved vSM-coverage and showed a trend toward reduction of microhemorrhage and abnormal vessel count. Conclusions: Thalidomide and lenalidomide stabilize the bAVM vessel wall and reduce microhemorrahge. Further studies are needed to determine whether these agents have a possible therapeutic value for patients.

Dosage-dependent requirement of BMP type II receptor for maintenance of vascular integrity

Blood ◽  
2007 ◽  
Vol 110 (5) ◽  
pp. 1502-1510 ◽  
Author(s):  
Dong Liu ◽  
Jian Wang ◽  
Bernd Kinzel ◽  
Matthias Müeller ◽  
Xiaohong Mao ◽  
...  
Keyword(s):  
Germ Line ◽  
Vascular Lesions ◽  
Type Ii ◽  
Cellular Mechanisms ◽  
Mural Cell ◽  
Vascular Integrity ◽  
Akt Activation ◽  
Adult Mice ◽  
Cell Coverage ◽  
Pulmonary Arterial

Abstract Germ-line mutations in bone morphogenic protein type II receptor (Bmpr2) confer susceptibility to pulmonary arterial hypertension (PAH), which is characterized by obstructive vascular lesions in small arteries. The molecular and cellular mechanisms that account for the etiology of this disorder remain elusive, as does the role of Bmpr2 in postnatal tissue homeostasis. Here we show that in adult mice, stably silencing Bmpr2 expression by RNA interference does not increase pulmonary arterial resistance but results in severe mucosal hemorrhage, incomplete mural cell coverage on vessel walls, and gastrointestinal hyperplasia. We present evidence that BMP receptor signaling regulates vascular remodeling during angiogenesis by maintaining the expression of endothelial guidance molecules that promote vessel patterning and maturation and by counteracting growth factor–induced AKT activation. Attenuation of this function may cause vascular dysmorphogenesis and predisposition to angioproliferative diseases. Our findings provide a mechanistic link between PAH and other diseases associated with the BMP/TGF-β pathways, such as hereditary hemorrhagic telangiectasia and juvenile polyposis syndrome.

scholarly journals Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL

2017 ◽  
Vol 214 (8) ◽  
pp. 2271-2282 ◽  
Author(s):  
Arturo I. Machuca-Parra ◽  
Alexander A. Bigger-Allen ◽  
Angie V. Sanchez ◽  
Anissa Boutabla ◽  
Jonathan Cardona-Vélez ◽  
...  
Keyword(s):  
Plasma Proteins ◽  
Small Vessel Disease ◽  
Cell Loss ◽  
Vascular Cognitive Impairment ◽  
Loss Of Function ◽  
Genetic Rescue ◽  
Mural Cell ◽  
Mural Cells ◽  
Cell Coverage ◽  
Necessary And Sufficient

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3. No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling.

scholarly journals Aberrant mural cell recruitment to lymphatic vessels and impaired lymphatic drainage in a murine model of pulmonary fibrosis

Blood ◽  
2012 ◽  
Vol 119 (24) ◽  
pp. 5931-5942 ◽  
Author(s):  
Anna-Katharina Meinecke ◽  
Nadine Nagy ◽  
Gabriela D'Amico Lago ◽  
Santina Kirmse ◽  
Ralph Klose ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Murine Model ◽  
Lymphatic Vessels ◽  
Lymphatic Drainage ◽  
Platelet Derived Growth Factor ◽  
Mural Cell ◽  
Cell Recruitment ◽  
Mural Cells ◽  
Perilymphatic Space

Abstract Pulmonary fibrosis is a progressive disease with unknown etiology that is characterized by extensive remodeling of the lung parenchyma, ultimately resulting in respiratory failure. Lymphatic vessels have been implicated with the development of pulmonary fibrosis, but the role of the lymphatic vasculature in the pathogenesis of pulmonary fibrosis remains enigmatic. Here we show in a murine model of pulmonary fibrosis that lymphatic vessels exhibit ectopic mural coverage and that this occurs early during the disease. The abnormal lymphatic vascular patterning in fibrotic lungs was driven by expression of platelet-derived growth factor B (PDGF-B) in lymphatic endothelial cells and signaling through platelet-derived growth factor receptor (PDGFR)–β in associated mural cells. Because of impaired lymphatic drainage, aberrant mural cell coverage fostered the accumulation of fibrogenic molecules and the attraction of fibroblasts to the perilymphatic space. Pharmacologic inhibition of the PDGF-B/PDGFR-β signaling axis disrupted the association of mural cells and lymphatic vessels, improved lymphatic drainage of the lung, and prevented the attraction of fibroblasts to the perilymphatic space. Our results implicate aberrant mural cell recruitment to lymphatic vessels in the pathogenesis of pulmonary fibrosis and that the drainage capacity of pulmonary lymphatics is a critical mediator of fibroproliferative changes.

scholarly journals EphrinB2-EphB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Maike Frye ◽  
Simon Stritt ◽  
Henrik Ortsäter ◽  
Magda Hernandez Vasquez ◽  
Mika Kaakinen ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Barrier Function ◽  
Lymphatic Vessel ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cell ◽  
Cell Junction ◽  
Adult Mice ◽  
Junction Protein ◽  
Vessel Integrity ◽  
And Function

Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. Here, we identified the transmembrane ligand EphrinB2 and its receptor EphB4 as critical homeostatic regulators of collecting lymphatic vessel integrity. Conditional gene deletion in mice revealed that EphrinB2/EphB4 signalling is dispensable for blood endothelial barrier function, but required for stabilization of lymphatic endothelial cell (LEC) junctions in different organs of juvenile and adult mice. Studies in primary human LECs further showed that basal EphrinB2/EphB4 signalling controls junctional localisation of the tight junction protein CLDN5 and junction stability via Rac1/Rho-mediated regulation of cytoskeletal contractility. EphrinB2/EphB4 signalling therefore provides a potential therapeutic target to selectively modulate lymphatic vessel permeability and function.

The Laryngeal Epithelium in Reflux

2011 ◽  
Vol 21 (3) ◽  
pp. 112-117 ◽  
Author(s):  
Elizabeth Erickson-Levendoski ◽  
Mahalakshmi Sivasankar
Keyword(s):  
Laryngopharyngeal Reflux ◽  
Critical Role ◽  
Structure And Function ◽  
Laryngeal Disease ◽  
Health And Disease ◽  
And Function ◽  
The Impact

The epithelium plays a critical role in the maintenance of laryngeal health. This is evident in that laryngeal disease may result when the integrity of the epithelium is compromised by insults such as laryngopharyngeal reflux. In this article, we will review the structure and function of the laryngeal epithelium and summarize the impact of laryngopharyngeal reflux on the epithelium. Research investigating the ramifications of reflux on the epithelium has improved our understanding of laryngeal disease associated with laryngopharyngeal reflux. It further highlights the need for continued research on the laryngeal epithelium in health and disease.

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