Sialic acid associated with αvβ3 integrin mediates HIV-1 Tat protein interaction and endothelial cell proangiogenic activation.

Sialic acid (NeuAc) is a major anion on endothelial cells (ECs) that regulates different biological processes including angiogenesis. NeuAc is present in the oligosaccharidic portion of integrins, receptors that interact with extracellular matrix components and growth factors regulating cell adhesion, migration, and proliferation. Tat is a cationic polypeptide that, once released by HIV-1(+) cells, accumulates in the extracellular matrix, promoting EC adhesion and proangiogenic activation by engaging α(v)β(3).

Substrate-immobilized HIV-1 Tat drives VEGFR2/α(v)β(3)-integrin complex formation and polarization in endothelial cells.

Objective: The HIV-1 transactivating factor (Tat) possesses features typical of both cell-adhesive and angiogenic growth factor (AGF) proteins, inducing endothelial cell (EC) adhesion and proangiogenic activation. Tat was exploited to investigate the events triggered by EC adhesion to substrate-bound AGF that lead to proangiogenic activation.

Methods And Results: Immobilized Tat induces actin cytoskeleton organization, formation of α(v)β(3) integrin(+)focal adhesion plaques, and recruitment of vascular endothelial growth factor receptor-2 (VEGFR2) in the ventral plasma membrane of adherent ECs.

alphavbeta3 Integrin-dependent antiangiogenic activity of resveratrol stereoisomers.

Angiogenesis is target for antineoplastic and chemopreventive therapies. The natural phytoalexin resveratrol is found in grapes and red wine as cis and trans stereoisomers. trans-Resveratrol shows antiangiogenic activity, but its mechanism of action is not fully elucidated.

The combination of Ezetimibe and Statin: a new treatment for hypercholesterolemia.

The combination of Simvastatin and Ezetimibe allows dual inhibition of both cholesterol production and absorption. This treatment approach allows achieving same low serum cholesterol levels with the administration of much lower doses of statins. This should reduce side effects, compared to statin only therapy, enabling more patients to achieve their LDL cholesterol treatment goals.

Integrin alphavbeta3 as a target for blocking HIV-1 Tat-induced endothelial cell activation in vitro and angiogenesis in vivo.

Objective: The transactivating factor (Tat) of HIV-1 binds to alphavbeta3 integrin present on endothelial cells contributing to neovascularization. Here, we investigated the biological consequences of Tat/alphavbeta3 interaction and the antagonist effect of an Arg-Gly-Asp (RGD)-based peptidomimetic.

Methods And Results: Binding of Tat to endothelial alphavbeta3 triggers focal adhesion kinase and nuclear factor-kappaB activation, leading to endothelial cell proliferation, membrane ruffling, and motility in vitro and neovascularization in vivo.

Antiangiogenic activity of semisynthetic biotechnological heparins: low-molecular-weight-sulfated Escherichia coli K5 polysaccharide derivatives as fibroblast growth factor antagonists.

Objective: Low-molecular-weight heparin (LMWH) exerts antitumor activity in clinical trials. The K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor. Chemical and enzymatic modifications of K5 polysaccharide lead to the production of biotechnological heparin-like compounds.

CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A.

The angiogenic activity of CXC-ELR(+) chemokines, including CXCL8/IL-8, CXCL1/macrophage inflammatory protein-2 (MIP-2), and CXCL1/growth-related oncogene-alpha in the Matrigel sponge angiogenesis assay in vivo, is strictly neutrophil dependent, as neutrophil depletion of the animals completely abrogates the angiogenic response. In this study, we demonstrate that mice deficient in the src family kinases, Hck and Fgr (hck(-/-)fgr(-/-)), are unable to develop an angiogenic response to CXCL1/MIP-2, although they respond normally to vascular endothelial growth factor-A (VEGF-A). Histological examination of the CXCL1/MIP-2-containing Matrigel implants isolated from wild-type or hck(-/-)fgr(-/-) mice showed the presence of an extensive neutrophil infiltrate, excluding a defective neutrophil recruitment into the Matrigel sponges.

Biological activity of substrate-bound basic fibroblast growth factor (FGF2): recruitment of FGF receptor-1 in endothelial cell adhesion contacts.

Substrate-bound FGF2 promotes endothelial cell adhesion by interacting with alpha(v)beta(3) integrin. Here, endothelial GM7373 cells spread and organize focal adhesion plaques on immobilized FGF2, fibronectin (FN), and vitronectin (VN). alpha(v)beta(3) integrin, paxillin, focal adhesion kinase, vinculin and pp60(src) localize in cell-substratum contact sites on FGF2, FN or VN.

Generation of biologically active angiostatin kringle 1-3 by activated human neutrophils.

The contribution of polymorphonuclear neutrophils (PMN) to host defense and natural immunity extends well beyond their traditional role as professional phagocytes. In this study, we demonstrate that upon stimulation with proinflammatory stimuli, human PMN release enzymatic activities that, in vitro, generate bioactive angiostatin fragments from purified plasminogen. We also provide evidence that these angiostatin-like fragments, comprising kringle domain 1 to kringle domain 3 (kringle 1-3) of plasminogen, are generated as a byproduct of the selective proteolytic activity of neutrophil-secreted elastase.

Cell membrane GM1 ganglioside is a functional coreceptor for fibroblast growth factor 2.

Free gangliosides bind fibroblast growth factor 2 (FGF2), thus preventing cell interaction and biological activity of the growth factor in endothelial cells. Here we investigated the role of cell-associated gangliosides in mediating the biological activity of FGF2. Treatment of endothelial cells of different origin with the ganglioside biosynthesis inhibitors fumonisin B1, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol or D-1-threo-1-phenyl-2-hexa-decanoylamino-3-pyrrolidino-1-propanol-HCl, impairs their capacity to proliferate when exposed to FGF2.