Biomedical subjects

Laurent Loufrani

Publications and source records attributed to Laurent Loufrani.

12 recordsLinked to original sources

PubMed2006

Key role of the NO-pathway and matrix metalloprotease-9 in high blood flow-induced remodeling of rat resistance arteries.

OBJECTIVE: Blood flow is altered in metabolic and ischemic diseases with dramatic consequences. Resistance arteries structure and function remodel in response to chronic blood flow changes through a mechanism remaining mainly unknown. We hypothesized that the NO pathway and matrix metalloproteases (MMPs) activation might play a role in flow (shear stress)-induced microvascular remodeling. METHODS AND RESULTS: Mesenteric resistance arteries were ligated to alter blood flow in vivo for 4 or 14 days: arteries were submitted to high (HF), low (LF), or normal flow (NF). Rats were treated with L-NAME, the angiotensin converting enzyme inhibitor perindopril or the MMPs inhibitor doxycycline. After 14 days, outward hypertrophic remodeling occurred in HF arteries in association with eNOS overexpression. MMP9 activity increased in the early phase (day 4). HF-remodeling was prevented by L-NAME, eNOS gene knockout, and doxycycline. L-NAME prevented eNOS overexpression and MMPs activation whereas doxycycline only prevented MMPs activation. In LF arteries diameter reduction was associated with a decreased eNOS expression without change in MMPs expression and activation. LF-remodeling was reduced by perindopril. CONCLUSIONS: In resistance arteries, high flow induced diameter enlargement and wall hypertrophy associated with the sequential activation of eNOS and MMP9.

Animals↗

PubMed2006

Carotid arterial stiffness, elastic fibre network and vasoreactivity in semicarbazide-sensitive amine-oxidase null mouse.

OBJECTIVE: We examined the arterial phenotype of semicarbazide-sensitive amine-oxidase null mouse (SSAO -/-) using various techniques including high resolution echotracking. METHODS AND RESULTS: SSAO -/- mice showed no change in arterial pressure under anesthesia. The in vivo arterial diameter, only measured in the carotid artery (CA), was higher in SSAO -/- than in SSAO +/+ animals. Elastic modulus-wall stress curves and CA rupture pressure were similar between SSAO -/- and +/+ mice, indicating no change in arterial wall stiffness or mechanical strength. There was no significant difference in insoluble elastin, total collagen content and elastic lamellar morphology between the two genotypes. No alteration in vascular reactivity was observed in aortic rings and mesenteric arteries from SSAO -/- mice. Aortic lysyl oxidase (LO) activity remained unaltered, indicating that SSAO invalidation is not accompanied by a compensatory increase in LO activity. CONCLUSION: This is the first functional study of arteries lacking SSAO. Our results indicate that SSAO -/- mice present an increased arterial diameter associated with normal arterial mechanical properties, suggesting that SSAO deficiency might contribute to arterial wall remodeling. However, these results argue against the hypothesis that SSAO intervenes in elastic fibre organization, elastin cross-linking processes and vasoreactivity.

Amine Oxidase (Copper-Containing)↗

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

High blood pressure reduction reverses angiotensin II type 2 receptor-mediated vasoconstriction into vasodilation in spontaneously hypertensive rats.

BACKGROUND: We have previously shown that angiotensin II type 2 receptor (AT(2)R) stimulation causes endothelium-dependent vasodilation that does not desensitize after chronic angiotensin II type 1 receptor (AT1R) blockade, suggesting a role for AT2R in antihypertensive treatment. METHODS AND RESULTS: We recorded mean arterial pressure (MAP) and investigated AT2R by Western blot analysis, immunohistochemistry, and function in isolated mesenteric resistance arteries (205 microm in diameter) from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) receiving the following for 4 weeks in drinking water: placebo, AT1R blockade (candesartan; 2 mg/kg per day), ACE inhibitor (perindopril; 3 mg/kg per day), nonselective vasodilator (hydralazine; 16 or 24 mg/kg per day), or candesartan plus hydralazine (16 mg/kg per day). In precontracted isolated arteries, AT2R stimulation (angiotensin II in the presence of candesartan) caused vasodilation in WKY rats (MAP=118 mm Hg) and vasoconstriction in SHR (MAP=183 mm Hg). In SHR treated with candesartan (MAP=146 mm Hg) or hydralazine (16 mg/kg per day; MAP=145 mm Hg), AT2R-induced contraction was reduced by 50%. In SHR treated with perindopril (MAP=125 mm Hg), AT2R stimulation induced vasodilation. In SHR treated with hydralazine (24 mg/kg per day; MAP=105 mm Hg) and in SHR treated with hydralazine (16 mg/kg per day) plus candesartan (MAP=102 mm Hg), an AT2R-mediated vasodilation was restored. Immunochemistry and Western blot analysis showed that AT2R expression, lower in SHR than in WKY rats, was restored to normal levels by treatments reducing arterial pressure in SHR. CONCLUSIONS: Our results suggest that in resistance arteries of SHR, (1) AT2R is downregulated by hypertension, and (2) specific and nonspecific antihypertensive treatments restore AT(2)R expression and vasodilator functions.

Animals↗

PubMed2005

Vasodilator treatment with hydralazine increases blood flow in mdx mice resistance arteries without vascular wall remodelling or endothelium function improvement.

BACKGROUND: Whereas dystrophin has a key role in striated muscle mechanotransduction, its role in vascular functions is not fully understood. In mice lacking dystrophin (mdx) both flow (shear stress)-mediated dilation (FMD) and vascular wall remodelling are decreased, suggesting a low capacity of the vasculature to adapt to metabolic needs. OBJECTIVE AND DESIGN: We assessed the capacity of a systemic vasodilator treatment to improve vascular remodelling and blood flow in mdx mice. We measured vascular structure and function in mesenteric resistance arteries (MRA) from control and mdx mice treated for 1 month with hydralazine. RESULTS: Although hydralazine did not significantly affect blood pressure, mesenteric blood flow was increased in control and mdx mice (150+/-25 to 194+/-30 and 110+/-26 to 143+/-18 microl/min; respectively; n=10/group). MRA (90 microm internal diameter, 75 mmHg) were isolated in vitro in arteriographs. Arterial diameter and FMD were significantly increased by hydralazine in control but not in mdx mice. Hydralazine also increased N-nitro-L-arginine methyl ester (L-NAME)-sensitive FMD in control mice, not in mdx mice. Pressure-, phenylephrine-, serotonin- and calcium-induced contraction, as well as acetylcholine- and sodium nitroprusside-induced dilation, were not affected by hydralazine whatever the strain. CONCLUSION: This study provides functional evidence that local blood flow could be improve by hydralazine in mdx mice despite a lack of vascular adaptation to flow. This study brings a new insight in the pathophysiology of dystrophin-related myopathies. Nevertheless, the consequences of an increased blood flow in non-adapted arteries remain unknown.

Acetylcholine↗

PubMed2004

Cyclooxygenase involvement in thromboxane-dependent contraction in rat mesenteric resistance arteries.

The influence of cyclooxygenase pathway activation following thromboxane-endoperoxide (TP) receptor stimulation was studied in rat mesenteric resistance arteries (n=6 to 10 per group). We studied isolated, perfused, and pressurized mesenteric resistance arteries (mean internal diameter 214 microm) using an arteriograph, enabling us to study arteries in physiological conditions of flow and pressure. Changes in diameter were continuously recorded, and contractions measured as internal diameter reduction. Release of cyclooxygenase pathway metabolites was also assessed by enzyme immunoassay (EIA) analysis of mesenteric bed perfusions. The thromboxane A2 (TxA2) analog U-46619 (1 micromol/L) induced a significant contraction (108 microm maximal diameter reduction). Inhibition by 3 chemically different cyclooxygenase inhibitors (ie, flurbiprofen, indomethacin, and aspirin) potently reduced the contraction to 27%, 25%, and 6% of control, respectively. The selective cyclooxygenase-1 inhibitor SC-58560 inhibited U-46619 contraction, whereas selective cyclooxygenase-2 inhibition (SC-58236) had no effect. Thromboxane synthase inhibition (furegrelate) did not affect U-46619-induced contraction, but it was reduced by cytosolic phospholipase A2 inhibition. Measurement of cyclooxygenase derivatives produced by the isolated mesenteric bed showed that PGE2 was produced after TxA2-receptor stimulation with U-46619. Exogenous prostaglandin E2 (in the presence of the TxA2 receptor antagonist SQ 29 548) and U-46619 contracted mesenteric arteries with a similar potency (EC50: 0.30 and 0.48 micromol/L, respectively). This study provides the first evidence that TxA2-receptor-dependent contraction in a resistant artery involved cyclooxygenase stimulation and, at least in part, a PGE2 formation. This mechanism of TxA2-dependent contraction in resistant arteries might be of importance in the understanding of diseases affecting resistant arteries and involving TxA2, such as hypertension.

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

PubMed2004

Absence of dystrophin in mice reduces NO-dependent vascular function and vascular density: total recovery after a treatment with the aminoglycoside gentamicin.

OBJECTIVE: Mutations in the dystrophin gene causing Duchenne's muscular dystrophy (DMD) lead to premature stop codons. In mice lacking dystrophin (mdx mice), a model for DMD, these mutations can be suppressed by aminoglycosides such as gentamicin. Dystrophin plays a role in flow (shear stress)-mediated endothelium-dependent dilation (FMD) in arteries. We investigated the effect of gentamicin on vascular contractile and dilatory functions, vascular structure, and density in mdx mice. METHODS AND RESULTS: Isolated mice carotid and mesenteric resistance arteries were mounted in arteriographs allowing continuous diameter measurements. Mdx mice showed lower nitric oxide (NO)-dependent FMD and endothelial NO synthase (eNOS) expression as well as decreased vascular density in gracilis and cardiac muscles compared with control mice. Treatment with gentamycin restored these parameters. In contrast, smooth muscle-dependent contractions as well as endothelium-dependent or -independent dilation were not affected by dystrophin deficiency or by gentamicin treatment. CONCLUSIONS: Dystrophin deficiency induces a selective defect in flow-dependent mechanotransduction, thus attenuating FMD and eNOS expression, and may contribute to low arteriolar density. These findings open important perspectives regarding the mechanism involved in the pathophysiology of genetic diseases related to premature stop codons such as DMD.

Animals↗

PubMed2002

Defect in microvascular adaptation to chronic changes in blood flow in mice lacking the gene encoding for dystrophin.

Dystrophin has a key role in striated muscle mechanotransduction. In mice lacking the gene encoding for dystrophin (mdx mice), the absence of dystrophin and several other proteins of the dystrophin-glycoprotein complex induces a defect in flow (shear stress)-mediated NO-dependent dilation (FMD). Because the endothelium is essential for the adaptation of arteries to chronic changes in blood flow, the long-term consequences of this vascular deficiency might affect flow-induced vascular remodeling. Thus, we submitted mouse mesenteric resistance arteries to chronic changes in flow by alternatively ligating arteries. Arteries were thus submitted to high flow (HF), low flow (LF), or normal flow. After 2 weeks, arteries were studied in vitro in an arteriograph. Increases in diameter (from 174+/-10 to 210+/-15 microm, pressure 75 mm Hg) found in HF arteries were not significant in mdx mice. Arterial diameters in LF arteries decreased similarly in control and mdx mice. FMD increased in HF arteries and decreased in LF arteries. FMD was not increased in HF arteries in mdx mice. NO-dependent FMD and NO synthase expression increased in the HF arteries of control mice but not in those of mdx mice. Dilatory and contractile tone, depending on the smooth muscle, was unaffected in HF arteries but decreased in LF arteries of both strains. We conclude that resistance arteries of mdx mice do not adapt properly to chronic changes in flow, inasmuch as the increases in diameter, endothelial NO synthase expression, and FMD did not occur in mdx mice submitted to HF for 2 weeks. This study suggests that blood flow regulation might be disturbed in dystrophin-related myopathies, possibly increasing organ damage.

Adaptation, Physiological↗

PubMed2002

Excessive microvascular adaptation to changes in blood flow in mice lacking gene encoding for desmin.

OBJECTIVE: Desmin, an intermediate filament, has a key role in the integrity of myocytes, and its absence induces cardiomyopathies. Mice lacking desmin (Des-/- group) exhibit microvascular dysfunction leading to smooth muscle hyporeactivity. We investigated the effect of the absence of desmin in mice (Des-/- mice versus Des+/+ mice) on the adaptation of mesenteric arteries to changes in blood flow. METHODS AND RESULTS: With the use of selective ligations of second-order mesenteric arteries, blood flow was either diminished (low flow [LF]) or elevated (high flow [HF]); respective LF to HF values were 136+/-18 to 206+/-29 microL/min for Des+/+ mice and 119+/-14 to 189+/-24 microL/min for Des-/-mice in daughter arteries. Two weeks after ligation, arteries were mounted in an arteriograph, allowing the measurement of diameter under controlled conditions of pressure and flow. In HF arteries, diameter changes in response to increases in pressure were higher in Des-/- mice than in Des+/+ mice. Conversely, in LF arteries, diameter was lower in Des-/- mice. Flow-dependent dilation was higher in HF arteries and lower in LF arteries than in control arteries. This adaptation was lower in Des-/- mice than in Des+/+ mice (11.6+/-3.1% versus 25.5+/-4.8% dilation, respectively). Endothelial NO synthase expression increased in HF arteries in both strains. CONCLUSIONS: These findings provide a demonstration of the role of the intermediate filament desmin in microvascular remodeling. This dysfunction might take place in desmin-related myopathies.

Adaptation, Physiological↗

PubMed2002

Chronic hydralazine improves flow (shear stress)-induced endothelium-dependent dilation in mouse mesenteric resistance arteries in vitro.

Flow (shear stress)-mediated dilation (FMD) plays a key role in the local control of vascular diameter and blood flow supply. Although vasodilator treatments improve FMD in diverse models of hypertension, FMD may also change in situations where systemic blood pressure is not affected. In pathological situations such as ischemia, local blood flow and vascular density are increased by vasodilators not affecting systemic blood pressure. As the mechanisms involved remain obscure, we studied FMD in resistance arteries from mice treated chronically (1 month) with hydralazine (200 mg/L in drinking water). Blood flow in mesenteric arteries of mice treated with hydralazine was significantly increased (130 +/- 15 to 169 +/- 27 microl/min, n = 10/group), whereas mean arterial blood pressure was not affected (79 +/- 5 vs 82 +/- 3 mm Hg in controls). Mesenteric resistance arteries (90 microm internal diameter, 75 mm Hg) were isolated and mounted in vitro in an arteriograph. Pressure (myogenic tone)-, phenylephrine-, and KCl-induced contractions, as well as acetylcholine- and sodium nitroprusside-induced dilations, were unaffected by hydralazine. Flow-mediated dilation in arteries from hydralazine-treated mice was significantly increased, especially for low flow values (up to sevenfold). L-NAME-sensitive and indomethacin-sensitive FMD were both increased by hydralazine. Passive arterial diameter increased and arterial wall thickness decreased after chronic hydralazine. This is the first functional evidence that flow (shear stress)-mediated dilation in resistance arteries is improved by a chronic treatment with a nonselective vasodilator. This arteriolar adaptation to a chronic increase in blood flow might be of importance in the pathophysiology of ischemic diseases.

Acetylcholine↗

PubMed2001

Selective microvascular dysfunction in mice lacking the gene encoding for desmin.

The intermediate filament desmin has a key role in the integrity and contractility of skeletal and cardiac myocytes. Its absence or aggregation leads to cardiomyopathies. In arteries desmin is distributed heterogeneously; vascular disorders might also occur in its absence. We studied endothelial and muscular functions in arteries from mice lacking desmin (des-/-), compared with control (des+/+). Carotid and mesenteric resistance arteries were mounted in vitro in arteriographs. Desmin was located exclusively in smooth muscle cells. In arteries from des-/- mice, pressure-induced (myogenic) tone was unchanged, but agonist-induced tone decreased in resistance arteries (no change in large arteries). Flow (shear stress)- and acetylcholine-induced, endothelium-dependent dilation, as well as endothelium-independent dilation, were also decreased in resistance arteries. To our knowledge, this is the first study of vascular contractile and dilatory functions in arteries lacking desmin. Although vascular reactivity was normal in large arteries, it decreased strongly in small resistance arteries. Thus, desmin is required in vascular smooth muscle cells and in resistance arteries, for efficient control of vascular tone and consequently for an optimal blood flow supply. This microvascular defect found in the absence of desmin might play a major role in myopathies seen in desmin-related diseases.

Animals↗

PubMedDate not supplied

p38 mitogen-activated protein kinase activation is required for thromboxane- induced contraction in perfused and pressurized rat mesenteric resistance arteries.

Thromboxane A(2) (TxA2) is a potent proaggregating, vasoconstrictor agent produced in many physiological and pathological situations. Although mitogen-activated protein (MAP) kinases [MAPK (ERK1/2 and p38)] have been shown to be activated after endoperoxide/thromboxane receptor (TP) stimulation, no study has investigated their potential role in resistance arteries, especially in physiological conditions of pressure and flow in which the arteries can contract. Thus, responses to TP stimulation by the stable agonist U46619 were studied in isolated rat mesenteric resistance arteries (inner diameter 262 +/- 5 microm) mounted in an arteriograph. Changes in diameter were recorded under physiological levels of flow (90 microl/min) and pressure (50 mm Hg). TP stimulation induced a concentration-dependent contraction (EC(50) value of 1.94 +/- 0.22 x 10(-7) M), without desensitization. U46619-induced contraction was inhibited by calcium entry blockade (nifedipine) and protein kinase C inhibition (GF109203X), but it was not affected by tyrosine kinase inhibition (tyrphostin A25). MAPKK (MEK) inhibition (PD98059) did not alter U46619-dependent contraction, although ERK1/2 MAPK were activated. By contrast, p38 MAPK inhibition (SB203580) dose-dependently inhibited the contraction, and Western blot analysis showed activation of p38 MAPK in arteries contracted with U46619. Activation of p38 MAPK by U46619 was inhibited by nifedipine and in the absence of extracellular calcium. This study brings new insights in the transduction pathway involved in the contractile response of resistance arteries to TxA2/endoperoxide receptor stimulation. This contraction requires p38 MAPK activation, but did not involve ERK1/2 MAPK activation although both were activated.

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