8 research outputs found
Serotonin receptor antagonism improves distal perfusion after hindlimb ischemia in ApoE-/-Mice
A New Synthetic FGF Receptor Antagonist Inhibits Arteriosclerosis in a Mouse Vein Graft Model and Atherosclerosis in Apolipoprotein E-Deficient Mice
<div><p>Objective</p><p>The role of fibroblast growth factors (FGFs) in the development of vascular diseases remains incompletely understood. The objective of this study was to examine the effects of a new small-molecule multi-FGF receptor blocker with allosteric properties, SSR128129E, on neointimal proliferation after a vein graft procedure in mice and on the development of atherosclerosis in atherosclerosis-prone apolipoprotein E (apoE)-deficient mice.</p> <p>Methods and Results</p><p>Vein grafts were performed in 3 month-old male C57BL6 mice. Segments of the vena cava were interposed at the level of the carotid artery. In SSR128129E (50 mg/kg/d)-treated animals, a dramatic decrease in neointimal proliferation was observed 2 and 8 weeks after the graft (72.5 %, p<0.01, and 47.8 %, p<0.05, respectively). Four-week old male apoE-deficient mice were treated with SSR128129E (50 mg/kg/d) for 3 and 5 months in comparison with a control group. SSR128129E treatment resulted in a reduction of lesion size in the aortic sinus (16.4 % (ns) at 3 months and 42.9 % (p<0.01) at 5 months, without any change in serum lipids. SSR128129 significantly reduced FGFR2 mRNA levels in the aortic sinus (p<0.05, n=5-6), but did not affect the mRNA expression levels of other FGF receptors or ligands.</p> <p>Conclusion</p><p>These studies indicate that FGFs have an important role in the development of vascular diseases like atherosclerosis and graft arteriosclerosis. These data suggest that inhibition of FGF receptors by compounds like SSR128129E might be useful as a new therapeutic approach for these vascular pathologies.</p> </div
Effect of SSR128129E on neointimal proliferation in the vein graft model.
<div><p>A-C: Effect on lesion macrophage content 2 weeks after surgery</p>
<p>Representative sections of vein grafts immunostained for macrophages (mac3) in control (A) and SSR128129E-treated mice (B). The size of the regions showing macrophage infiltration was determined by image analysis (C, n= 4 per group).</p>
<p>D-I: Effect on neointimal proliferation 8 weeks after surgery.</p>
<p>Representative sections of vein grafts stained by Masson’s trichrome in control (D) and SSR128129E-treated mice (E). The area of neointimal proliferation was determined by image analysis (F, n= 8-11 per group). Smooth muscle content is shown in representative sections of vein grafts labelled for α-actin in control (G) and SSR128129E-treated mice (H). Smooth muscle content as determined by the area of α-actin staining was determined by image analysis (I, n= 8-11 per group).</p></div
Lesion morphology and size in the aortic sinus of 6 month old apoE-deficient mice.
<p>Lesion morphology as shown in representative slices of aortic sinus stained by Masson’s trichrome in 6 month-old control apoE-KO (A) and SSR128129E-treated mice (B). Aortic sinus lesion size was determined by image analysis in 6 month-old apoE-deficient mice (C, n= 8 per group). </p
mRNA expression levels of FGF receptors and ligands in the aortic sinus.
<p>mRNA levels were determined by quantitative PCR of extracts of the aortic sinus of 6 month-old normal mice (C57BL/6, white bars), apoE-deficient mice (light green bars) and SSR128129-treated apoE-deficient mice (light blue bars). Bars represent the mean±SEM of the data, n=5-6. (*: p<0.05 , **: p<0.01).</p
A New Synthetic FGF Receptor Antagonist Inhibits Arteriosclerosis in a Mouse Vein Graft Model and Atherosclerosis in Apolipoprotein E-Deficient Mice
P2Y(4) nucleotide receptor: a novel actor in post-natal cardiac development.
Communication between endothelial cells and cardiomyocytes is critical for cardiac development and regeneration. However the mechanisms involved in these endothelial-cardiomyocyte interactions remain poorly understood. Nucleotides are released within the heart, especially under ischemia or pressure overload. The function of P2Y nucleotide receptors in cardiac development has never been investigated. Here we show that adult P2Y(4)-null mice display microcardia. P2Y(4) nucleotide receptor is expressed in cardiac endothelial cells but not in cardiomyocytes. Loss of P2Y(4) in cardiac endothelial cells strongly inhibits their growth, migration and PDGF-B secretion in response to UTP. Proliferation of microvessels and cardiomyocytes is reduced in P2Y(4)-null hearts early after birth, resulting in reduced heart growth. Our study uncovers mouse P2Y(4) receptor as an essential regulator of cardiac endothelial cell function, and illustrates the involvement of endothelial-cardiomyocyte interactions in post-natal heart development. We also detected P2Y(4) expression in human cardiac microvessels. P2Y(4) receptor could constitute a therapeutic target to regulate cardiac remodelling and post-ischemic revascularisation.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe
Inhibition of Tumor Angiogenesis and Growth by a Small-Molecule Multi-FGF Receptor Blocker with Allosteric Properties.
Receptor tyrosine kinases (RTK) are targets for anticancer drug development. To date, only RTK inhibitors that block orthosteric binding of ligands and substrates have been developed. Here, we report the pharmacologic characterization of the chemical SSR128129E (SSR), which inhibits fibroblast growth factor receptor (FGFR) signaling by binding to the extracellular FGFR domain without affecting orthosteric FGF binding. SSR exhibits allosteric properties, including probe dependence, signaling bias, and ceiling effects. Inhibition by SSR is highly conserved throughout the animal kingdom. Oral delivery of SSR inhibits arthritis and tumors that are relatively refractory to anti-vascular endothelial growth factor receptor-2 antibodies. Thus, orally-active extracellularly acting small-molecule modulators of RTKs with allosteric properties can be developed and may offer opportunities to improve anticancer treatment