Biomedical subjects

Laurent Loufrani

Publications and source records attributed to Laurent Loufrani.

5 recordsLinked to original sources

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↗