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Biomedical subjects

Bernard I Lévy

Publications and source records attributed to Bernard I Lévy.

At least 19 recordsLinked to original sources
PubMed2006

RhoA activation and interaction with Caveolin-1 are critical for pressure-induced myogenic tone in rat mesenteric resistance arteries.

OBJECTIVE: Myogenic tone, which has a major role in the regulation of local blood flow, refers to the ability of vascular smooth muscle to adapt its contractility to changes in transmural pressure. Although Rho-kinase is involved in myogenic tone, the pathway involved remains unclear, especially concerning translocation to the plasma membrane and activation of RhoA. As caveolae have a key role in the signal transduction of membrane-bound proteins, we tested the hypothesis that RhoA might be activated by pressure and that its activation might involve caveolin-1, which has been shown to be involved in vascular functions. METHODS: Myogenic tone was studied in isolated rat mesenteric resistance arteries (118+/-15 microm internal diameter with a pressure of 75 mmHg) submitted to pressure steps (25, 75, and 150 mmHg). Pharmacological blockade of caveolae or RhoA-Rho-kinase pathway was assessed by confocal microscopy in pressurized arteries to analyze protein co-localization and by co-immunoprecipitation in order to confirm protein interactions. Caveolin-1-deficient mice were used to confirm the role of the protein in myogenic tone. RESULTS: Pressure-induced myogenic tone was significantly reduced by RhoA inactivation with TAT-C3 (90.5% inhibition at 150 mmHg) and by the Rho-kinase inhibitor Y27632 (91.8% inhibition at 150 mmHg). In arteries pressurized at 150 mmHg, RhoA was localized to the plasma membrane (localization by confocal microscopy and increased quantity of RhoA in the membrane fraction after protein extraction). Thus, translocation of RhoA to the plasma membrane was associated with pressure-induced tone. In addition, caveolae disruption with methyl-beta-cyclodextrin reduced myogenic tone by 66% at 150 mmHg. Further, myogenic tone was significantly reduced to 24% of control in caveolin-1-deficient mice (active tone was 32.3+/-2.8 microm and 9.1+/-3.7 microm in +/+ and -/- mice, respectively, n = 5 per group), suggesting a key role of caveolin-1 in myogenic tone. Finally, RhoA and caveolin-1 co-immunoprecipitation and co-localization significantly increased when myogenic tone developed at 150 mmHg (co-localization showed 26+/-13% merging at 25 mmHg versus 97+/-21% at 150 mmHg, n = 5). Co-immunoprecipitation was prevented by TAT-C3 and by methyl beta-cyclodextrin. CONCLUSION: RhoA activation is critical for the development of myogenic tone in resistance arteries. This activation induced translocation of RhoA to the plasma membrane within caveolae, where the interaction of RhoA with caveolin-1 leads selectively to the activation of a Rho-kinase-dependent force development.

Actins↗
PubMed2006

Increase in vascular permeability and vasodilation are critical for proangiogenic effects of stem cell therapy.

BACKGROUND: Proangiogenic cell therapy based on administration of bone marrow-derived mononuclear cells (BMCs) or endothelial progenitor cells (EPCs) is now under investigation in humans for the treatment of ischemic diseases. However, mechanisms leading to the beneficial effects of BMCs and EPCs remain unclear. METHODS AND RESULTS: BMC- and CD34+-derived progenitor cells interacted with ischemic femoral arteries through SDF-1 and CXCR4 signaling and released nitric oxide (NO) via an endothelial nitric oxide synthase (eNOS)-dependent pathway. BMC-induced NO production promoted a marked vasodilation and disrupted vascular endothelial-cadherin/beta-catenin complexes, leading to increased vascular permeability. NO-dependent vasodilation and hyperpermeability were critical for BMC infiltration in ischemic tissues and their proangiogenic potential in a model of hindlimb ischemia in mice. CONCLUSIONS: Our results propose a new concept that proangiogenic progenitor cell activity does not rely only on their ability to differentiate into endothelial cells but rather on their capacity to modulate the function of preexisting vessels.

Animals↗
PubMed2006

Tetrapeptide AcSDKP induces postischemic neovascularization through monocyte chemoattractant protein-1 signaling.

BACKGROUND: We investigated the putative proangiogenic activity and molecular pathway(s) of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) in a model of surgically induced hindlimb ischemia. METHODS AND RESULTS: Hindlimb ischemia was induced by femoral artery ligature and an osmotic minipump was implanted subcutaneously to deliver low (0.12 mg/kg per day) or high (1.2 mg/kg per day) doses of AcSDKP, for 7 or 21 days. Angiography scores, arteriole density, capillary number, and foot perfusion were increased at day 21 in the high-dose AcSDKP-treated mice (by 1.9-, 1.8-, 1.3-, and 1.6-fold, respectively) compared with control animals (P<0.05, P<0.01, P<0.01, respectively). AcSDKP treatment for 24 hours upregulated the monocyte chemoattractant protein-1 (MCP-1) mRNA and protein levels by 1.5-fold in cultured endothelial cells (P<0.01). In the ischemic hindlimb model, administration of AcSDKP also enhanced MCP-1 mRNA levels by 90-fold in ischemic leg (P<0.001) and MCP-1 plasma levels by 3-fold (P<0.001 versus untreated ischemic control mice). MCP-1 levels upregulation were associated with a 2.3-fold increase in the number of Mac3-positive cells in ischemic area of AcSDKP-treated mice (P<0.001 versus untreated animals). Interestingly, AcSDKP-induced monocyte/macrophage infiltration and postischemic neovascularization was fully blunted in MCP-1-deficient animals. CONCLUSIONS: AcSDKP stimulates postischemic neovascularization through activation of a proinflammatory MCP-1-related pathway.

Animals↗
PubMed2006

Comparative effect of aspirin and clopidogrel on arterial function in CHF.

BACKGROUND: By inhibiting prostaglandins, aspirin may be deleterious in congestive heart failure (CHF) and/or partially counteract the efficacy of angiotensin-converting enzyme inhibitors (ACEI). Conversely, clopidogrel has no effect on prostaglandin metabolism. The aim of this study was to prospectively investigate the effect of aspirin and clopidogrel on arterial functional properties in CHF patients treated with ACEI. METHODS: Forty-five patients with stable NYHA class II-IV CHF (64.0+/-15.5 years), ejection fraction <40%, were included in this prospective double-blind study and randomized to receive aspirin 325 mg/day or clopidogrel 75 mg/day for 14 days. Reflected wave assessed by radial applanation tonometry and pulse wave velocity (PWV) were measured at day 0 and day 14. RESULTS: Aspirin resulted in an increase in the augmentation index of the reflected wave (Delta=+3.5+/-5.2%, p=0.005) and the height above the shoulder of the reflected wave (Delta=+1.7+/-3.1 mm Hg, p=0.023), without statistically variation in PWV. Conversely, clopidogrel had no effect on the same parameters (p=0.512, p=0.677 and 0.801, respectively). Overall, variations in the augmentation index of reflected wave significantly differed when compared aspirin with clopidogrel (p=0.0261). CONCLUSION: This study demonstrates the existence of a negative effect of aspirin 325 mg/day when compared to clopidogrel 75 mg/day on arterial functional properties in CHF patients treated with ACEI.

Aged↗
PubMed2005

Involvement of RhoA/Rho kinase pathway in myogenic tone in the rabbit facial vein.

Myogenic tone (MT), a fundamental stretch-sensitive vasoconstrictor property of resistance arteries and veins, is a key determinant of local blood flow regulation. We evaluated the pathways involved in MT development. The role of the RhoA/Rho kinase, p38 MAP kinase, and HSP27 in MT was investigated in the rabbit facial vein (RFV), previously shown to possess MT at a pressure level equivalent to 20 mm Hg. Venous MT is poorly understood, although venous diseases affect a large proportion of the population. Stretched RFV are characterized by a temperature-sensitive MT, which is normal at 39 degrees C but fails to develop at 33 degrees C. This allows for the discrimination of the pathways involved in MT from the multiple pathways activated by stretch. Isolated RFV segments were mounted in organ baths and stretched. Temperature was then set at 33 degrees C or 39 degrees C. MT was associated to the translocation of RhoA to the plasma membrane and the Rho kinase inhibitor Y27632 decreased stretch-induced MT by 93.1+/-4.9%. MT was also associated to an increase in p38 (131.0+/-12.5% at 39 degrees C versus 100% at 33 degrees C) and HSP27 phosphorylation (196.1+/-13.3% versus 100%), and the p38 MAP kinase inhibitor SB203580 decreased MT by 36.5+/-8.1%. (39 degrees C, compared with RFV stretched at 33 degrees C). Finally, phosphorylation of p38 was blocked by Y27632 and HSP27 phosphorylation was inhibited by SB203580 and Y27632. Thus, MT and the associated p38 and HSP27 phosphorylation seem to depend on RhoA/Rho kinase activation in stretch RFV.

Amides↗
PubMed2005

Circadian fluctuations of macular edema in patients with morning vision blurring: correlation with arterial pressure and effect of light deprivation.

PURPOSE: This study explored the causes of vision fluctuations in patients with chronic macular edema. METHODS: Fifteen patients (16 eyes) with vision blurring at awakening due to post-central retinal vein occlusion (CRVO) macular edema underwent three examination sessions over 24 hours (at 7 PM, immediately after awakening at 7 AM, and at 7 PM), which comprised assessment of Early Treatment Diabetic Retinopathy Study score and measurement of macular thickness (MT) by optical coherence tomography. Ocular perfusion pressure was calculated from ambulatory arterial pressure measurement. In addition, after the 7 AM measurements, the patients were randomly selected for monocular light deprivation during the day to evaluate the role of retinal illumination in these fluctuations. RESULTS: Circadian fluctuation of MT was documented in all patients. At 7 AM, mean visual acuity (VA) was worse (mean +/- SD of the difference: 6.5 +/- 7.2 points; P < 0.002) and mean MT was higher (57.4 +/- 34 microm; P < 0.001) than at 7 PM. Fluctuations of MT were correlated to fluctuation of arterial pressure (P = 0.05), but were not influenced by monocular light deprivation. CONCLUSIONS: In most patients complaining of visual fluctuations due to macular edema secondary to CRVO, MT and VA were found to undergo a circadian cycle. These short-term anatomic and functional variations were associated with arterial pressure variations (that is, macular thickening was inversely correlated to the arterial pressure drop during the night), but were not due to light deprivation.

Adult↗
PubMed2005

[The importance of microcirculation and tissue perfusion in hypertension].

The importance of abnormalities observed in the microcirculation of hypertensive subjects is being increasingly recognised. These microvascular changes may be central to the development of end-organ damage brought about by hypertension, including ischaemic heart disease. The primary function of the microcirculation is to supply oxygen and nutrients to myocardial tissue, and it also has an important role in regulating coronary blood flow. Some 70-90% of the overall peripheral resistance of the circulatory system arises at the level of the microcirculation. In hypertension, thickening of the microvascular walls occur, with narrowing of the lumen, so that eventually the vessel is functionally occluded. The result is a reduction in the number of arterioles or capillaries in a given vascular bed. Such changes have been seen in the structure and density of the microvasculature of heart muscle, the conjunctiva and retina, and in the kidneys. In hypertension a vicious circle occurs, with an increase in blood pressure producing a rise in resistance in the microcirculation, leading to further elevation of blood pressure. New techniques for exploring the coronary microcirculation have shown that microvascular damage results in reductions of coronary vasodilator reserve, an important predictor of clinical deterioration and death. With studies showing that impairment of microcirculation occurs early in patients with hypertension, there would seem to be a need for new therapeutic perspectives in hypertension, concentrating on preventing or reversing changes to the microvasculature of affected organs.

Blood Flow Velocity↗
PubMed2004

Flow-dependent dilation mediated by endogenous kinins requires angiotensin AT2 receptors.

The vascular kallikrein-kinin system contributes to about one third of flow-dependent dilation in mice carotid arteries, by activating bradykinin B2 receptors coupled to endothelial nitric oxide (NO) release. Because the bradykinin/NO pathway may mediate some of the effects of angiotensin II AT2 receptors, we examined the possible contribution of AT2 receptors to the kinin-dependent response to flow. Changes in outer diameter after increases in flow rate were evaluated in perfused arteries from wild-type animals (TK+/+) and in tissue kallikrein-deficient mice (TK-/-) in which the presence of AT2 receptor expression was verified. Saralasin, a nonselective angiotensin II receptor antagonist, impaired significantly flow-induced dilation in TK+/+, whereas it had no effect in TK-/- mice. In both groups, blockade of AT1 receptors with losartan or candesartan did not affect the response to flow. Inhibition of AT2 receptors with PD123319 reduced significantly flow-induced dilation in TK+/+ mice, but had no significant effect in TK-/- mice. Combining PD123319 with the bradykinin B2 receptor antagonist HOE-140 had no additional effect to AT2 receptor blockade alone in TK+/+ arteries. Flow-dependent-dilation was also impaired in AT2 receptor deficient mice (AT2-/-) when compared with wild-type littermates. Furthermore, HOE-140 significantly reduced the response to flow in the AT2+/+, but not in AT2-/- mice. In conclusion, this study demonstrates that the presence of functional AT2 receptors is necessary to observe the contribution of the vascular kinin-kallikrein system to flow-dependent dilation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2004

Impairment in ischemia-induced neovascularization in diabetes: bone marrow mononuclear cell dysfunction and therapeutic potential of placenta growth factor treatment.

Mechanisms that hinder ischemia-induced neovascularization in diabetes remain poorly understood. We hypothesized that endogenous bone marrow mononuclear cell (BM-MNC) dysfunction may contribute to the abrogated postischemic revascularization reaction associated with diabetes. We first analyzed the effect of diabetes (streptozotocin, 40 mg/kg) on BM-MNC pro-angiogenic potential in a model of surgically induced hindlimb ischemia. In nondiabetic animals, transplantation of BM-MNCs isolated from nondiabetic animals raised the ischemic/nonischemic angiographic score, capillary number, and blood flow recovery by 1.8-, 2.7-, and 2.2-fold, respectively, over that of PBS-injected nondiabetic animals (P < 0.05). Administration of diabetic BM-MNCs also improved the neovascularization reaction in ischemic hindlimbs of nondiabetic mice but to a lesser extent from that observed with nondiabetic BM-MNC transplantation. In diabetic mice, injection of nondiabetic BM-MNCs was still more efficient than that of diabetic BM-MNCs. Such BM-MNC dysfunction was associated with the impairment of diabetic BM-MNC capacity to differentiate into endothelial progenitor cells (EPCs) in vitro and to participate in vascular-like structure formation in a subcutaneous Matrigel plug. Placenta growth factor (PlGF) administration improved by sixfold the number of EPCs differentiated from diabetic BM-MNCs in vitro and enhanced ischemic/nonischemic angiographic score, capillary number and blood flow recovery by 1.9-, 1.5- and 1.6-fold, respectively, over that of untreated diabetic animals (P < 0.01). Endogenous BM-MNC pro-angiogenic potential was affected in diabetes. Therapeutic strategy based on PlGF administration restored such defects and improved postischemic neovascularization in diabetic mice.

Angiography↗
PubMed2004

Minimally invasive, in vivo exploration of mouse small artery reactivity.

The aim of the study was to investigate in vivo arterial reactivity in the mouse hind limb using Orthogonal Polarisation Spectral (OPS) imaging, which delivers high-contrast images of vascular beds by visualizing red blood cells. After minimal skin invasion of anesthetized mice, the OPS probe was placed on the hind limb continuously superfused with physiological saline solution. Then, the response of the saphenous artery (average luminal diameter 127 +/- 3 microm; n = 15) to topical application of increasing concentrations of acetylcholine or phenylephrine was examined. Mean carotid arterial blood pressure was unaffected during the experiment. The basal diameter decreased by 70% during exposure to phenylephrine (pD2: 5.65 +/- 0.08; n = 9), while acetylcholine augmented basal diameter up to 199% (pD2: 6.55 +/- 0.12; n = 6). Application of sodium nitroprusside did not further increase arterial diameter following acetylcholine exposure. After washing out, arterial luminal diameters returned to initial values. Second exposure to vasoactive agents demonstrated that changes in diameter were reproducible with time and not different between left and right saphenous arteries. Thus, OPS imaging is an in vivo dye-free, simple and minimally invasive approach, which provides unique information regarding the behavior of vascular network within conditions of cellular and physiological homeostasis.

Acetylcholine↗
PubMed2004

[The renin-angiotensin system and post-ischemic angiogenesis].

This article summarizes the main mechanisms responsible for the ischemia-induced neovascularization. Growth factors and inflammatory agents are the most powerful actors in the neo-vascularization process. Numerous other factors have been shown to modulate blood vessel growth. Among these, we have tested the potential effect of angiotensin II in several in vivo models of angiogenesis. Angiotensin II has pro-angiogenic effects via its AT1 subtype receptor whereas the AT2 angiotensin II receptor has pro-apoptotic and anti-angiogenic properties. Besides its effect on angiotensin II formation, some angiotensin-converting-enzyme inhibitors have pro-angiogenic effect by increasing the local concentration of bradykinin in ischemic tissues and, thus, by activation of its B2 receptor and then NO release. These besides the "classical" gene and cellular therapies designed for the treatment of pathological tissue ischemia, alternative strategies using new pharmacological properties of drugs acting on the renin angiotensin system are likely to be possible.

Angiotensin II↗
PubMed2003

Uterine artery structural and functional changes during pregnancy in tissue kallikrein-deficient mice.

OBJECTIVE: Tissue kallikrein (TK) participates in acute flow-induced dilatation (FID) of large arteries. We investigated whether TK deficiency blunts FID and alters chronic flow-related arterial structural and functional changes in resistance-sized muscular arteries. METHODS AND RESULTS: Vasomotor responses and structural parameters were determined in uterine arteries isolated from nonpregnant, 18- to 19-day pregnant, and 7-day postpartum TK-/- and TK+/+ littermate mice. In TK-/- mice, values of diameter, medial cross-sectional area (CSA), myogenic tone, and dilatation in response to acetylcholine were comparable to those values in TK+/+ mice, but FID (0 to 100 microL/min) was significantly reduced (55+/-4% versus 85+/-4% in TK+/+ mice). In both mouse strains, pregnancy resulted in significant increases in diameter and medial CSA and in the Nw-nitro-l-arginine methyl ester-sensitive component of FID. By 7 days after pregnancy, uterine arterial diameter and CSA values no longer differed from nonpregnant values, and FID was markedly reduced in TK-/- and TK+/+ mice. CONCLUSIONS: These observations (1) confirm at the level of resistance arteries the key role of TK in FID and (2) indicate that TK deficiency does not compromise arterial remodeling and changes in the contribution of NO to FID during and after pregnancy.

Animals↗
PubMed2003

Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice.

We hypothesized that formation of advanced glycation end products (AGEs) associated with diabetes reduces matrix degradation by metalloproteinases (MMPs) and contributes to the impairment of ischemia-induced angiogenesis. Mice were treated or not with streptozotocin (40 mg/kg) and streptozotocin plus aminoguanidine (AGEs formation blocker, 50 mg/kg). After 8 weeks of treatment, hindlimb ischemia was induced by right femoral artery ligature. Plasma AGE levels were strongly elevated in diabetic mice when compared with control mice (579 +/- 21 versus 47 +/- 4 pmol/ml, respectively; P < 0.01). Treatment with aminoguanidine reduced AGE plasma levels when compared with untreated diabetic mice (P < 0.001). After 28 days of ischemia, ischemic/nonischemic leg angiographic score, capillary density, and laser Doppler skin-perfusion ratios were 1.4-, 1.5-, and 1.4-fold decreased in diabetic mice in reference to controls (P < 0.01). Treatment with aminoguanidine completely normalized ischemia-induced angiogenesis in diabetic mice. We next analyzed the role of proteolysis in AGE formation-induced hampered neovascularization process. After 3 days of ischemia, MMP-2 activity and MMP-3 and MMP-13 protein levels were increased in untreated and aminoguanidine-treated diabetic mice when compared with controls (P < 0.05). Despite this activation of the MMP pathway, collagenolysis was decreased in untreated diabetic mice. Conversely, treatment of diabetic mice with aminoguanidine restored collagenolysis toward levels found in control mice. In conclusion, blockade of AGE formation by aminoguanidine normalizes impaired ischemia-induced angiogenesis in diabetic mice. This effect is probably mediated by restoration of matrix degradation processes that are disturbed as a result of AGE accumulation.

Angiography↗