Neuropilins 1 and 2 mediate neointimal hyperplasia and re-endothelialization following arterial injury

AIMS: Neuropilins 1 and 2 (NRP1 and NRP2) play crucial roles in endothelial cell migration contributing to angiogenesis and vascular development. Both NRPs are also expressed by cultured vascular smooth muscle cells (VSMCs) and are implicated in VSMC migration stimulated by PDGF-BB, but it is unknown whether NRPs are relevant for VSMC function in vivo. We investigated the role of NRPs in the rat carotid balloon injury model, in which endothelial denudation and arterial stretch induce neointimal hyperplasia involving VSMC migration and proliferation. METHODS AND RESULTS: NRP1 and NRP2 mRNAs and proteins increased significantly following arterial injury, and immunofluorescent staining revealed neointimal NRP expression. Down-regulation of NRP1 and NRP2 using shRNA significantly reduced neointimal hyperplasia following injury. Furthermore, inhibition of NRP1 by adenovirally overexpressing a loss-of-function NRP1 mutant lacking the cytoplasmic domain (ΔC) reduced neointimal hyperplasia, whereas wild-type (WT) NRP1 had no effect. NRP-targeted shRNAs impaired, while overexpression of NRP1 WT and NRP1 ΔC enhanced, arterial re-endothelialization 14 days after injury. Knockdown of either NRP1 or NRP2 inhibited PDGF-BB-induced rat VSMC migration, whereas knockdown of NRP2, but not NRP1, reduced proliferation of cultured rat VSMC and neointimal VSMC in vivo. NRP knockdown also reduced the phosphorylation of PDGFα and PDGFβ receptors in rat VSMC, which mediate VSMC migration and proliferation. CONCLUSION: NRP1 and NRP2 play important roles in the regulation of neointimal hyperplasia in vivo by modulating VSMC migration (via NRP1 and NRP2) and proliferation (via NRP2), independently of the role of NRPs in re-endothelialization

VEGF (Vascular Endothelial Growth Factor) Induces NRP1 (Neuropilin-1) Cleavage via ADAMs (a Disintegrin and Metalloproteinase) 9 and 10 to Generate Novel Carboxy- Terminal NRP1 Fragments That Regulate Angiogenic Signaling

OBJECTIVE: NRP1(neuropilin-1) acts as a coreceptor for VEGF (vascular endothelial growth factor) with an essential role in angiogenesis. Recent findings suggest that posttranslational proteolytic cleavage of VEGF receptors may be an important mechanism for regulating angiogenesis, but the role of NRP1 proteolysis and the NRP1 species generated by cleavage in endothelial cells is not known. To characterize NRP1 proteolytic cleavage in endothelial cells, determine the mechanism, and investigate the role of NRP1 cleavage in regulation of endothelial cell function. APPROACH AND RESULTS: NRP1 species comprising the carboxy (C)-terminal and transmembrane NRP1 domains but lacking the ligand-binding A and B regions are constitutively expressed in endothelial cells. Generation of these C-terminal domain NRP1 proteins is upregulated by phorbol ester and Ca2+ ionophore, and reduced by pharmacological inhibition of metalloproteinases, by small interfering RNA-mediated knockdown of 2 members of ADAM (a disintegrin and metalloproteinase) family, ADAMs 9 and 10, and by a specific ADAM10 inhibitor. Furthermore, VEGF upregulates expression of these NRP1 species in an ADAM9/10-dependent manner. Transduction of endothelial cells with adenoviral constructs expressing NRP1 C-terminal domain fragments inhibited VEGF-induced phosphorylation of VEGFR2 (VEGF receptor tyrosine kinase)/KDR and decreased VEGF-stimulated endothelial cell motility and angiogenesis in coculture and aortic ring sprouting assays. CONCLUSIONS: These findings identify novel NRP1 species in endothelial cells and demonstrate that regulation of NRP1 proteolysis via ADAMs 9 and 10 is a new regulatory pathway able to modulate VEGF angiogenic signaling

Emerging Roles for Neuropilin-2 in Cardiovascular Disease

Cardiovascular disease, the leading cause of death worldwide, is predominantly associated with atherosclerosis. Atherosclerosis is a chronic inflammatory disease characterised by the narrowing of large to medium-sized arteries due to a build-up of plaque. Atherosclerotic plaque is comprised of lipids, extracellular matrix, and several cell types, including endothelial, immune, and vascular smooth muscle cells. Such narrowing of the blood vessels can itself restrict blood flow to vital organs but most severe clinical complications, including heart attacks and strokes, occur when lesions rupture, triggering the blood to clot and obstructing blood flow further down the vascular tree. To circumvent such obstructions, percutaneous coronary intervention or bypass grafts are often required; however, re-occlusion of the treated artery frequently occurs. Neuropilins (NRPs), a multifunctional family of cell surface co-receptors, are expressed by endothelial, immune, and vascular smooth muscle cells and are regulators of numerous signalling pathways within the vasculature. Here, we review recent studies implicating NRP2 in the development of occlusive vascular diseases and discuss how NRP2 could be targeted for therapeutic intervention

Microporous Biodegradable Films Promote Therapeutic Angiogenesis

Peripheral arterial disease and critical limb ischemia are common symptoms of cardiovascular disease. Vascular surgery is used to create a bypass around occluded blood vessels to improve blood flow to ischemic muscle, thus avoiding the need for amputation. Attempts to vascularize tissues by therapeutic angiogenesis using delivery of exogenous angiogenic agents are underwhelming. A material-based approach that provides an endogenous stimulus capable of promoting angiogenesis and increased tissue perfusion would provide a paradigm shift in treatment options available. It is reported here that microporous biodegradable films produced using thermally induced phase separation provide a localized biophysical stimulus of proangiogenic genes in vivo that is associated with increased blood vessel density and restoration of blood flow to ischemic tissue. These findings show, for the first time, that acellular, nonfunctionalized biodegradable biomaterials can provide an innovative, material-based approach for therapeutic angiogenesis to enhance tissue reperfusion in vivo

Planetary Nebulae Kinematics in M31

We present kinematics of 135 planetary nebulae in M31 from a survey covering 3.9 square degrees and extending out to 15 kpc from the southwest major axis and more than 20 kpc along the minor axis. The majority of our sample, even well outside the disk, shows significant rotational support (mean line-of-sight velocity 116 km/s). We argue that these PN belong to the outer part of M31's large de Vaucouleurs bulge. Only five PN have velocities clearly inconsistent with this fast rotating bulge. All five may belong to tidal streams in M31's outer halo. One is projected on the Northern Spur, and is counter-rotating with respect to the disk there. Two are projected along the major axis at X=-10 kpc and have M32-like velocities; they could be debris from that galaxy. The remaining two halo PN are located near the center of the galaxy and their velocities follow the gradient found by Ibata et al. (2004), implying that these PN could belong to the Southern Stream. If M31 has a non-rotating, pressure-supported halo, we have yet to find it, and it must be a very minor component of the galaxy.Comment: accepted to ApJ; main body of paper is 36 pages, including 14 figure

Spectrophotometry of HII Regions, Diffuse Ionized Gas and Supernova Remnants in M31: The Transition from Photo- to Shock-Ionization

We present results of KPNO 4-m optical spectroscopy of discrete emission-line nebulae and regions of diffuse ionized gas (DIG) in M31. Long-slit spectra of 16 positions in the NE half of M31 were obtained over a 5-15 kpc range in radial distance from the center of the galaxy. The spectra have been used to confirm 16 supernova remnant candidates from the Braun & Walterbos (1993) catalog. The slits also covered 46 HII regions which show significant differences among the various morphological types (center-brightened, diffuse, rings). Radial gradients in emission-line ratios such as [OIII]/H$\beta$ and [OII]/[OIII] are observed most prominently in the center-brightened HII regions. These line ratio trends are either much weaker or completely absent in the diffuse and ring nebulae. The line ratio gradients previously seen in M31 SNRs (Blair, Kirshner, & Chevalier 1981; 1982) are well reproduced by our new data. The spectra of center-brightened HII regions and SNRs confirm previous determinations of the radial abundance gradient in M31. We use diagnostic diagrams which separate photoionized gas from shock-ionized gas to compare the spectral properties of HII regions, SNRs and DIG. This analysis strengthens earlier claims (Greenawalt, Walterbos, & Braun 1997) that the DIG in the disk of M31 is photoionized by a dilute radiation field.Comment: 45 pages, 9 figures, 7 tables, to appear in the Astronomical Journal (December 1999

Human Herpesvirus 8 in Healthy Blood Donors, Argentina

Fil: Pérez, Celeste L. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Departamento de Virología. Servicio Cultivo de Tejidos; Argentina.Fil: Tous, Mónica I. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas; Argentina.Fil: Zala, Norma. Hospital de Enfermedades Infecciosas “Francisco J Muñiz,”; Argentina.Fil: Camino, Sofia. Hospital de Enfermedades Infecciosas “Francisco J Muñiz,”; Argentina

Integrating multiple satellite observations into a coherent dataset to monitor the full water cycle – application to the Mediterranean region

The Mediterranean region is one of the climate hotspots where the climate change impacts are both pronounced and documented. The HyMeX (Hydrometeorological Mediterranean eXperiment) aims to improve our understanding of the water cycle from the meteorological to climate scales. However, monitoring the water cycle with Earth observations (EO) is still a challenge: EO products are multiple, and their utility is degraded by large uncertainties and incoherences among the products. Over the Mediterranean region, these difficulties are exacerbated by the coastal/mountainous regions and the small size of the hydrological basins. Therefore, merging/integration techniques have been developed to reduce these issues. We introduce here an improved methodology that closes not only the terrestrial but also the atmospheric and ocean budgets. The new scheme allows us to impose a spatial and temporal multi-scale budget closure constraint. A new approach is also proposed to downscale the results from the basin to pixel scales (at the resolution of 0.25∘). The provided Mediterranean WC budget is, for the first time, based mostly on observations such as the GRACE water storage or the netflow at the Gibraltar Strait. The integrated dataset is in better agreement with in situ measurements, and we are now able to estimate the Bosporus Strait annual mean netflow.</p

Luminous AGB stars in nearby galaxies. A study using Virtual Observatory tools

Aims. This study focuses on very luminous Mbol<-6.0 mag AGB stars with J-Ks>1.5 mag and H-Ks>0.4 mag in the LMC, SMC, M31, and M33 from 2MASS data. Methods.The data were taken from the 2MASS All-Sky Point Source catalogue archive. We used Virtual Observatory tools and took advantage of its capabilities at various stages in the analysis. Results. It is well known that stars with the colors we selected correspond mainly to carbon stars. Although the most luminous AGBs detected here contain a large number of carbon stars,they are not included in existing catalogues produced from data in the optical domain, where they are not visible since they are dust-enshrouded. A comparison of the AGB stars detected with combined near and mid-infrared data from MSX and 2MASS in the LMC shows that 10% of the bright AGB stars are bright carbon stars never detected before and that the other 50% are OH/IR oxygen rich stars, whereas the 40% that remain were not cross-matched. Conclusions. The catalogues of the most luminous AGB stars compiled here are an important complement to existing data. In the LMC, these bright AGB stars are centrally located, whereas they are concentrated in an active star-formation ring in M31. In the SMC and M33, there are not enough of them to draw definite conclusions, although they tend to be centrally located. Their luminosity functions are similar for the four galaxies we studied.Comment: 16 pages, 12 figures, 4 tables (Appendix A), accepted in A&