Jean-sébastien Silvestre - Academia.edu (original) (raw)

Papers by Jean-sébastien Silvestre

Circulation research, Jan 3, 2015

Optimal outcome after myocardial infarction depends on a coordinated healing response in which bo... more Optimal outcome after myocardial infarction depends on a coordinated healing response in which both debris removal and repair of the myocardial extracellular matrix play a major role. However, adverse remodeling and/or excessive inflammation can promote heart failure, positioning leucocytes as central protagonists and potential therapeutic targets in tissue repair and wound healing after MI. In this study, we examined the role of TREM-1 (Triggering Receptor Expressed on Myeloid cells-1) in orchestrating the inflammatory response that follows MI. TREM-1, expressed by neutrophils and mature monocytes, is an amplifier of the innate immune response. Following infarction, TREM-1 expression is up-regulated in ischemic myocardium in mice and humans. Trem-1 genetic invalidation or pharmacologic inhibition using of a synthetic peptide (LR12) dampens myocardial inflammation, limits neutrophils recruitment and MCP-1 production, thus reducing classical monocytes mobilization to the heart. It al...

We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization... more We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization. The response to unilateral femoral artery ligation was studied in wild-type or gp91 phox -deficient control or type 1 diabetic mice or in animals treated with the anti-oxidant N-acetyl-L-cysteine (NAC) or with in vivo electrotransfer of a plasmid encoding dominant-negative Rac1 (50 g) for 21 days. Postischemic neovascularization was reduced in diabetic mice in association with down-regulated vascular endothelial growth factor-A protein levels. In diabetic animals vascular endothelial growth factor levels and postischemic neovascularization were restored to nondiabetic levels by the scavenging of reactive oxygen species (ROS) by NAC administration or the inhibition of ROS generation by gp91 phox deficiency or by administration of dominant-negative Rac1. Finally, diabetes reduced the ability of adherent bone marrow-derived mononuclear cells (BM-MNCs) to differentiate into endothelial progenitor cells. Treatment with NAC (3 mmol/L), apocynin (200 mol/L), or the p38MAPK inhibitor LY333351 (10 mol/L) up-regulated the number of endothelial progenitor cell colonies derived from diabetic BM-MNCs by 1.5-, 1.6-, and 1.5-fold, respectively (P < 0.05). In the ischemic hindlimb model, injection of diabetic BM-MNCs isolated from NACtreated or gp91 phox -deficient diabetic mice increased neovascularization by ϳ1.5-fold greater than un-treated diabetic BM-MNCs (P < 0.05). Thus, inhibition of NADPH oxidase-derived ROS overproduction improves the angiogenic and vasculogenic processes and restores postischemic neovascularization in type 1 diabetic mice.

Objectives—As SDF-1 and its cognate receptor CXCR4 play a key role in the survival and mobilizati... more Objectives—As SDF-1 and its cognate receptor CXCR4 play a key role in the survival and mobilization of immature cells, we examined whether preconditioning of endothelial progenitor cells (EPCs) with SDF-1 could further promote their capacity to enhance angiogenesis. Methods and Results—EPC exposure to 100 ng/mL SDF-1 for 30 min induced a proangiogenic phenotype, with cell migration and differentiation into vascular

Ischemia induces both hypoxia and inflammation that trigger angiogenesis. The inflammatory reacti... more Ischemia induces both hypoxia and inflammation that trigger angiogenesis. The inflammatory reaction is modulated by production of anti-inflammatory cytokines. This study examined the potential role of a major anti-inflammatory cytokine, interleukin (IL)-10, on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by artery femoral occlusion in both C57BL/6J IL-101/1 and IL-10-/- mice. After 28 days, angiogenesis

Background—Adipose tissue development and remodeling are closely associated with the growth of va... more Background—Adipose tissue development and remodeling are closely associated with the growth of vascular network. We hypothesized that adipose tissue may contain progenitor cells with angiogenic potential and that therapy based on adipose tissue-derived progenitor cells administration may constitute a promising cell therapy in patients with ischemic disease. Methods and Results—In mice, cultured stromal-vascular fraction (SVF) cells from adipose tissue have

Nature Medicine, 2005

angiogenesis and requires integrin-mediated signaling. We now show that an integrin-binding prote... more angiogenesis and requires integrin-mediated signaling. We now show that an integrin-binding protein initially described in milk-fat globule, MFG-E8 (also known as lactadherin), is expressed in and around blood vessels and has a crucial role in VEGFdependent neovascularization in the adult mouse. Using neutralizing antibodies and lactadherin-deficient animals, we show that lactadherin interacts with αvβ3 and αvβ5 integrins and alters both VEGF-dependent Akt phosphorylation and neovascularization. In the absence of VEGF, lactadherin administration induced αvβ3and αvβ5-dependent Akt phosphorylation in endothelial cells in vitro and strongly improved postischemic neovascularization in vivo. These results show a crucial role for lactadherin in VEGFdependent neovascularization and identify lactadherin as an important target for the modulation of neovascularization.

Journal of the American College of Cardiology, 2008

Our goal was to demonstrate that microparticles (MPs) are the endogenous signal leading to neoves... more Our goal was to demonstrate that microparticles (MPs) are the endogenous signal leading to neovessel formation through CD40 ligation in human atherosclerotic plaques.

Diabetes, 2010

OBJECTIVE-Diabetic retinopathy is associated with progressive retinal capillary activation and pr... more OBJECTIVE-Diabetic retinopathy is associated with progressive retinal capillary activation and proliferation, leading to vision impairment and blindness. Microparticles are submicron membrane vesicles with biological activities, released following cell activation or apoptosis. We tested the hypothesis that proangiogenic microparticles accumulate in vitreous fluid in diabetic retinopathy.

Circulation Research, 2003

Vascular endothelial growth factors (VEGFs) and their receptors have emerged as central regulator... more Vascular endothelial growth factors (VEGFs) and their receptors have emerged as central regulators of the angiogenic process. However, involvement of VEGF-B, one of these factors, in angiogenesis remains obscure. Mice received subcutaneous injection of Matrigel alone or Matrigel with human recombinant protein rhVEGF-B 167 or with rhVEGF-A 165 . After 14 days, cell ingrowth in the Matrigel plug was increased by 2.0-and 2.5-fold in rhVEGF-B 167treated and rhVEGF-A 165 -treated mice, respectively (PϽ0.01), in association with a raise in phospho-Akt/Akt (1.8-fold, PϽ0.01) and endothelial NO synthase (eNOS) (1.80-and 1.60-fold, respectively; PϽ0.05) protein levels measured by Western blot. VEGF-B-induced cell ingrowth was impaired by treatment with NOS inhibitor (N G -nitro-L-arginine methyl ester; L-NAME, 10 mg/kg per day). Treatment with neutralizing antibody directed against the VEGF-B receptor VEGF-R1 (anti-VEGFR1, 10 g) completely abrogated VEGF-B-related effects. Proangiogenic effect of VEGF-B was confirmed in a mouse model of surgically induced hindlimb ischemia. Plasmids containing human form of VEGF-A (phVEGF-A 165 ) or VEGF-B (phVEGF-B 167 or phVEGF-B 186 ) were administered by in vivo electrotransfer. Angiographic score at day 28 showed significant improvement in ischemic/nonischemic leg ratio by 1.4-and 1.5-fold in mice treated with phVEGF-B 167 and phVEGF-B 186 , respectively (PϽ0.05). Laser Doppler perfusion data also evidenced a 1.5-fold increase in phVEGF-B 167 -treated and phVEGF-B 186 -treated mice (PϽ0.05). Such an effect was associated with an upregulation of phospho-Akt/Akt and eNOS protein levels in the ischemic legs and was hampered by treatment with anti-VEGFR1. This study demonstrates for the first time that VEGF-B, in part through its receptor VEGF-R1, promotes angiogenesis in association with an activation of Akt and eNOS-related pathways. (Circ Res. 2003;93:114-123.) Key Words: vascular endothelial growth factor-B Ⅲ angiogenesis Ⅲ ischemia Ⅲ endothelial nitric oxide Original

Circulation Research, 2001

Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhib... more Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effect of ACE inhibition may be mediated, in part, by bradykinin (BK) B 2 -receptor pathway. This study therefore examined the neovascularization induced by ACE inhibitor treatment in B 2 receptor-deficient mice (B 2 Ϫ/Ϫ ) in a model of surgically induced hindlimb ischemia. After artery femoral occlusion, wild-type and B 2

Circulation, 2009

Background-We hypothesized that microparticles (MPs) released after ischemia are endogenous signa... more Background-We hypothesized that microparticles (MPs) released after ischemia are endogenous signals leading to postischemic vasculogenesis. Methods and Results-MPs from mice ischemic hind-limb muscle were detected by electron microscopy 48 hours after unilateral femoral artery ligation as vesicles of 0.1-to 1-m diameter. After isolation by sequential centrifugation, flow cytometry analyses showed that the annexin V ϩ MP concentration was 3.5-fold higher in ischemic calves than control muscles (1392Ϯ406 versus 394Ϯ180 annexin V ϩ MPs per 1 mg; PϽ0.001) and came mainly from endothelial cells (71% of MPs are CD 144ϩ ). MPs isolated from ischemic muscles induced more potent in vitro bone marrow-mononuclear cell (BM-MNC) differentiation into cells with endothelial phenotype than those isolated from control muscles. MPs isolated from atherosclerotic plaques were ineffective, whereas those isolated from apoptotic or interleukin-1␤-activated endothelial cells also promoted BM-MNC differentiation. Interestingly, MPs from ischemic muscles produced more reactive oxygen species and expressed significantly higher levels of NADPH oxidase p47 (6-fold; PϽ0.05) and p67 subunits (16-fold; PϽ0.001) than controls, whereas gp91 subunit expression was unchanged. BM-MNC differentiation was reduced by 2-fold with MPs isolated from gp91-deficient animals compared with wild-type mice (PϽ0.05). MP effects on postischemic revascularization were then examined in an ischemic hind-limb model. MPs isolated from ischemic muscles were injected into ischemic legs in parallel with venous injection of BM-MNCs. MPs increased the proangiogenic effect of BM-MNC transplantation, and this effect was blunted by gp91 deficiency. In parallel, BM-MNC proangiogenic potential also was reduced in ABCA1 knockout mice with impaired vesiculation. Conclusion-MPs produced during tissue ischemia stimulate progenitor cell differentiation and subsequently promote postnatal neovascularization.

Circulation, 1999

Background-This study analyzed the regulation and the role of the cardiac steroidogenic system in... more Background-This study analyzed the regulation and the role of the cardiac steroidogenic system in myocardial infarction (MI). Methods and Results-Seven days after MI, rats were randomized to untreated infarcted group or spironolactone-(20 and 80 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ), losartan-(8 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ), spironolactone plus losartan-, and L-NAME-(5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) treated infarcted groups for 25 days. Sham-operated rats served as controls. In the noninfarcted myocardium of the left ventricle (LV), MI raised aldosterone synthase mRNA (the terminal enzyme of aldosterone synthesis) by 2.0-fold and the aldosterone level by 3.7-fold. Conversely, MI decreased 11␤-hydroxylase mRNA (the terminal enzyme of corticosterone synthesis) by 2.4-fold and the corticosterone level by 1.9-fold. MI also induced a 1.9-fold increase in cardiac angiotensin II level. Such cardiac regulations were completely prevented by treatment of the infarcted heart with losartan. The MI-induced collagen deposition in noninfarcted LV myocardium was prevented by 1.6-fold by both low and high doses of spironolactone and by 2.5-fold by losartan. In addition, norepinephrine level was unchanged in infarcted heart but was attenuated by both losartan and spironolactone treatments. Conclusions-MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This increase is mediated primarily by cardiac angiotensin II via AT 1 -subtype receptor and may be involved in post-MI ventricular fibrosis and in control of tissue norepinephrine concentration. (Circulation. 1999;99:2694-2701.)

The American Journal of Pathology, 2006

The American Journal of Pathology, 2007

Lactadherin is a secreted extracellular matrix protein expressed in phagocytes and contributes to... more Lactadherin is a secreted extracellular matrix protein expressed in phagocytes and contributes to the removal of apoptotic cells. We examined lactadherin expression in brain sections of patients with or without Alzheimer's disease and studied its role in the phagocytosis of amyloid ␤-peptide (A␤). Cells involved in Alzheimer's disease, including vascular smooth muscle cells, astrocytes, and microglia, showed a time-related increase in lactadherin production in culture. Quantitative analysis of the level of lactadherin showed a 35% reduction in lactadherin mRNA expression in the brains of patients with Alzheimer's disease (n ‫؍‬ 52) compared with age-matched controls (n ‫؍‬ 58; P ‫؍‬ 0.003). Interestingly, lactadherin protein was detected in the brains of patients with Alzheimer's disease and controls, with low expression in areas rich in senile plaques and marked expression in areas without A␤ deposition. Using surface plasmon resonance, we observed a direct pro-tein-protein interaction between recombinant lactadherin and A␤ 1-42 peptide in vitro. Lactadherin deficiency or its neutralization using specific antibodies significantly prevented A␤ 1-42 phagocytosis by murine and human macrophages.

Archives of Cardiovascular Diseases Supplements, 2014