Published online before print November 14, 2002, doi: 10.1161/01.RES.0000047505.11002.81
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Defect in Microvascular Adaptation to Chronic Changes in Blood Flow in Mice Lacking the Gene Encoding for Dystrophin
From Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 541 (L.L., D.H.), IFR Circulation-Paris-Nord, Paris VII University, and the Department of Physiology (B.I.L.), AP-HP-Hôpital Lariboisière, Paris, France.
Correspondence to D. Henrion, PhD, INSERM U541, Hôpital Lariboisière, 41 Bd de la Chapelle, 75475 Paris, cedex 10, France. E-mail daniel.henrion{at}larib.inserm.fr
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Abstract |
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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 µm, 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.
Key Words: microcirculation • cytoskeleton • Duchenne muscular dystrophy • dystrophin • endothelium
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Introduction |
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Avariety of mutations in the dystrophin gene result in severe myopathies, among which Duchenne and Becker muscular dystrophies are the most common. Dystrophin belongs to a large complex of membrane-associated proteins. Dystrophin ensures a link between the membrane proteins of the complex (dystroglycans and sarcoglycans) and the cytoskeletal proteins, such as actin.1,2 Thus, dystrophin has a key role in the transduction of physical forces in striated muscles2 and possibly in vascular smooth muscle cells.3 Recently, we have found dystrophin in human, rat, and mouse endothelial cells.4 Furthermore, we have observed that endothelium-dependent vasorelaxation induced by flow (shear stress) is strongly, and selectively, attenuated in mice lacking dystrophin and several other proteins of the dystrophin glycoprotein complex (mdx mice).4 This endothelial dysfunction might have serious consequences in dystrophin-related myopathies, because it might be associated to a deficient blood flow supply. Indeed, flow (shear stress)–mediated vasodilation (FMD) has a key role in the short-term control of vascular tone5 by inducing the release of endothelium-derived vasoactive agents.6–9 A decreased FMD is a common marker of endothelial dysfunction, and most vasodilator treatments improve FMD in various models of hypertension.10 FMD may also change in situations in which systemic blood pressure is not affected. In physiological situations, such as exercise training, FMD in skeletal muscle arteries is improved and is associated with an increased production of NO and prostanoids.11,12 In pathological situations, such as ischemia, vasodilator drugs improve local blood flow and vascular density without affecting systemic blood pressure.13 Chronic changes in blood flow induce the remodeling of the vascular wall.14 Nevertheless, the mechanism of this shear stress–induced vascular remodeling remains controversial in the microcirculation. Indeed, a chronic increase in blood flow induces an increase in diameter, thus allowing a normalization of the shear stress and an optimal blood flow supply.15 In large or compliance arteries, such as the aorta or the carotid artery, flow-induced NO is the main determinant of vascular remodeling.16 In resistance arteries, chronic NO synthase (NOS) inhibition does not prevent flow-induced remodeling,17 although endothelial NOS expression increases in arteries submitted to high flow (HF).18 We induced changes in blood flow in mesenteric resistance arteries from mdx mice. These mice represent a model of selective defect in FMD without other large changes in vascular functions and without hypertension.4 This lower sensitivity to shear stress allowed us to hypothesize that resistance arteries in mdx mice might not adapt properly to chronic changes in blood flow.
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Materials and Methods |
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Arterial Ligation in Mouse Mesenteric Arteries
Adult (3-month-old) male mdx mice and their controls (C57-Bl10, Iffa-Credo, L’Arbresle, France) were anesthetized (pentobarbital sodium, 50 mg/kg IP) and submitted to surgery to modify blood flow in the mesenteric arteries, as previously described in rats14 and adapted to mice.19 Ligations were performed with 7-0 silk surgical thread and were applied on the second-order mesenteric artery side branch as shown in Figure 1, top (24 mice per group). Some mice were sham-operated (ie, submitted to the same surgical intervention but without arterial ligation; 10 to 12 mice per group).
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In a preliminary group of experiments, surgery was performed to change flow, but the mice were used 1, 2, or 3 weeks later. This was done to determine the time course of the remodeling induced by flow in the mouse mesenteric artery (8 mice per group).
In another group of experiments (8 mice per group), ligations were positioned at different places along the arcading arteries so that flow in the HF arteries could be high (L4), midrange (L3), or low (L2). After 2 weeks, blood flow and arterial diameter were determined as described below.
The procedure followed in the care and euthanasia of the study animals was in accordance with the European Community Standards on the Care and Use of Laboratory Animals (Ministère de l’Agriculture, France, authorization No. 00577).
Blood Flow Measurements in Mesenteric Arteries
After 2 weeks, the animals were anesthetized with sodium pentobarbital (50 mg/kg IP). Body temperature was maintained at 37.5°C by a thermostatically controlled heating platform. The right carotid artery was cannulated to measure blood pressure.4,9,20 A medial laparotomy was then performed, and a section of the ileum was extracted and spread over a gauze swab that had been dampened with a sterile physiological salt solution (PSS). A segment of a first-order mesenteric artery side branch was dissected free of fat and connective tissue under a dissection microscope (Figure 1, top). By use of a micromanipulator, a transit-time ultrasonic flow probe (0.5-mm V series, Transonic Systems) was placed around the artery. Flow was determined with a T106 flowmeter (Transonic Systems). A zero-flow reading was obtained by softly clamping the artery under investigation. Then, flow was determined and recorded (Biopac) over a period of 10 minutes (each flow value was the average of at least 3 minutes of recording). Flow through the ligated and nonligated mesenteric arteries and through the first-order mesenteric artery side branches of control animals was determined as described above. After flow measurements were determined, the mesenteric arteries were carefully removed from the animal and kept in ice-cold physiological solution.
Pressure and Flow (Shear Stress)–Dependent Tone in Isolated Arteries
Segments of mesenteric arteries (2 to 3 mm long, 10 mice per group) were cannulated at both ends in a video-monitored perfusion system21 (LSI) as previously described.4,9,20 Briefly, arteries were bathed in PSS (pH 7.4, PO2 160 mm Hg, PCO2 37 mm Hg). Pressure was controlled by a servo-perfusion system, and flow was generated by a peristaltic pump. Diameter changes and changes in wall thickness were measured when intraluminal pressure was increased from 10 to 150 mm Hg. We then set pressure at 75 mm Hg, and flow was increased in steps. At the end of each experiment, the arteries were perfused and superfused with a Ca2+-free PSS containing EGTA (2 mmol/L) and sodium nitroprusside (10 µmol/L). Pressure steps were then repeated to determine the arterial passive diameter.4,20,22
By use of wire myographs as previously described,20 other segments of artery (2 mm long) were used for the following experiments: Cumulative concentration-response curves were obtained to phenylephrine and sodium nitroprusside. Sodium nitroprusside concentration-response curves were obtained after preconstriction of the artery with phenylephrine (1 µmol/L). Data were expressed as percent dilation of phenylephrine-induced preconstriction.
In a separate series of experiments (8 mice per group), arteries were mounted in the arteriograph as described above, pressure was set at 75 mm Hg, and the arteries were fixed in a 10% buffered formaldehyde solution, as previously described.4
Western Blot Analysis of eNOS
In a separate series of experiments (6 mice per group), arterial ligations were performed as described above, and arteries were collected after 2 weeks. Arterial tissues (1 first-order artery per experimental condition for normal-flow [NF] and HF arteries; otherwise, two low-flow [LF] arteries were pooled per mouse) were then homogenized (Ultrasonic Processor, Bioblock Scientific). Proteins (10 µg total protein from each sample) were separated by SDS-PAGE (Mini gel protean II system [Bio-Rad], 100 V, with 300 mL of 25 mmol/L Tris, 192 mmol/L glycine, and 0.1% SDS) using a 4% stacking gel followed by a 7% running gel. After migration, proteins were transferred (50 V, overnight, 4°C, with 800 mL of 25 mmol/L Tris, 192 mmol/L glycine, and 10% methanol) to PVDF blotting membranes (Immobilon-P, Millipore). Membranes were then washed in TBS-T buffer (composed of 10 mmol/L Tris/base pH 7.5, 0.1 mol/L NaCl, 1 mmol/L EDTA, and 0.1% Tween 20) and blocked for 2 hours at room temperature (5% fat-free dry milk in TBS-T). Membranes were incubated for 90 minutes at room temperature with the primary antibody (Santa Cruz Biotechnology, dilution 1:500 in TBS-T), washed again (3 times for 10 minutes), and incubated with horseradish peroxidase–conjugated secondary antibody (Santa Cruz Biotechnology, 90 minutes at room temperature, dilution 1:2000). Membranes were washed (3 times for 10 minutes) and endothelial NOS (eNOS or NOS III) was visualized using the ECL-Plus Chemiluminescence kit (Amersham).
Statistical Analysis
Results were expressed as mean±SEM. The concentration of agonist required to induce half the maximum response (EC50 and IC50) and the maximal response were calculated for each artery submitted to phenylephrine or sodium nitroprusside.20 Significance of the differences between groups was determined by ANOVA (1-factor ANOVA or ANOVA for consecutive measurements, when appropriate). Means were compared by paired t test or by the Bonferroni test for multigroup comparisons. Values of P<0.05 were considered to be significant.
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Results |
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Body weight and mean arterial blood pressure were not significantly affected by the ligations in either mdx or control mice (Table).
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As shown in Figure 1 (top), arteries were designated as HF, LF, and NF. Blood flow was significantly increased in HF mesenteric resistance arteries in mdx and control mice (Table). This increase in blood flow was higher in control mice (66±10%) than in mdx mice (39±7%). In LF arteries, flow rate was too low to be determined, although flow was visible in the lumen of the vessels. Blood flow in sham-operated mice was not altered in either strain (Table).
In isolated mesenteric resistance arteries, stepwise increases in pressure induce diameter (passive diameter) enlargement when measured in Ca2+-free PSS+EGTA (2 mmol/L) (Figure 2). In control mice, passive arterial diameter was higher in HF arteries than in NF arteries, whereas in LF arteries, it was highly decreased. This effect was significant 2 weeks after ligation in HF arteries and 1 week after ligation in LF arteries (Figure 1, bottom).
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In another series of experiments, arterial ligations were performed in both control and mdx mice. After 2 weeks, arterial diameter was determined in vitro. In HF arteries, the increase in diameter was higher in control mice than in mdx mice (Figure 2, top). This represented a 29±5% increase in diameter under a pressure of 75 mm Hg in control mice versus 5±3% in mdx mice (Figure 2, bottom). In LF arteries, the decrease in passive arterial diameter was similar in mdx and control mice (Figure 2, top). The arterial passive diameter in NF arteries was similar in mdx and control mice (Figure 2, top). NF arteries had the same diameter as arteries from sham-operated mice (data not shown). Thus, in the following groups of experiments, HF and LF arteries were compared with NF arteries from the same mouse, and no more sham-operated mice were used.
Changing the position of the ligatures allowed modulating blood flow in the HF artery. In control mice, three groups were obtained in which flow in the HF artery increased by 25%, 40%, and 66% (L2, L3, and L4, respectively; Figure 2, bottom). In these conditions, the increase in diameter was proportional to the increase in blood flow (Figure 2, bottom). On the other hand, in mdx mice, the increase in diameter remained low although the increase in flow was proportional to the position of the ligatures. As shown in Figure 2 (bottom), comparable flow increases were produced in L3 for control mice and L4 for mdx mice, but the latter produced less change in diameter (20±3% versus 5±3% increase in diameter for L3 [control] versus L4 [mdx], respectively; n=10 per group, P<0.001). These measurements also allowed for determining a correlation between the changes in flow and the corresponding changes in diameter in the HF arteries. In control mice, a significant correlation was found between the increase in blood flow and the increase in diameter (r2=0.64, P=0.001, n=22). In mdx mice, no significant correlation was found (r2=0.035, P=0.65, n=12).
Arterial wall thickness was measured in arteries fixed under a pressure of 75 mm Hg. In control mice, arterial wall thickness was higher in HF than NF arteries (8 mice per group). NF arteries had a wall thickness of 6.1±0.7 µm and a medial thickness of 4.0±0.5 µm compared with 8.0±0.8 µm (P=1.7 [not significant]) and 5.7±0.6 µm (P<0.05), respectively, in HF arteries. In HF compared with NF arteries in mdx mice, wall thickness (6.0±0.5 versus 6.4±0.7 µm, respectively) and medial thickness (3.7±0.6 versus 4.4±0.7 µm, respectively) were not significantly increased.
In isolated mesenteric resistance arteries, stepwise increases in flow induced a significant arterial dilation (Figure 3). Flow-mediated dilation was significantly higher in HF than NF arteries in control mice but not in mdx mice (Figure 3). In LF arteries, flow-mediated dilation was significantly lower than that in NF arteries in both mdx and control mice (Figure 3). Inhibition of NO synthesis (NG-nitro-L-arginine methyl ester [L-NAME]) significantly attenuated flow-mediated dilation (Figure 4). In control mice, L-NAME was more efficient in HF than in NF arteries (90±6% versus 61±8% decrease in flow-mediated dilation, respectively; flow 100 µL/min). L-NAME had the same efficiency in LF and NF arteries (data not shown). The attenuation of flow-mediated dilation by L-NAME was lower in mdx mice than in control mice (in NF arteries, 36±5% versus 61±8% decrease in flow-mediated dilation, respectively; flow 100 µL/min, calculated from data shown in Figure 4). In mdx mice, L-NAME had the same efficiency in HF, LF, and NF arteries (Figure 4, data not shown for LF arteries).
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The expression of eNOS (NOS III) was significantly increased in HF arteries compared with NF arteries in control mice (Figure 5). In LF arteries, NOS III expression was not different from that in NF arteries (Figure 5). In NF arteries, NOS III expression was significantly lower in mdx mice than in control mice (Figure 5). In mdx mice, NOS III expression was not significantly different in HF and LF arteries compared with NF arteries (Figure 5).
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Phenylephrine (Figure 6) produced a concentration-dependent contraction in mouse mesenteric resistance arteries. Phenylephrine-induced contraction was similar in HF and LF arteries in both mdx and control mice. On the other hand, phenylephrine-induced contraction was significantly lower in LF arteries than in NF arteries in both mouse strains (in control mice, the maximal contraction was shifted from 0.31±0.06 to 0.14±0.04 mN/mm, and the IC50 was shifted from 1.1±0.4 to 2.6±0.7 µmol/L [n=10, P<0.001]; in mdx mice, the maximal contraction was shifted from 0.32±0.07 to 0.9±0.05 mN/mm, and the IC50 was shifted from 1.7±0.6 to 4.5±1.6 µmol/L [n=10, P<0.001]). Phenylephrine-induced contraction was not significantly different in mdx and control mice.
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Sodium nitroprusside (Figure 6) induced a concentration-dependent dilation of mouse mesenteric resistance arteries precontracted with phenylephrine. Sodium nitroprusside–induced dilation was similar in HF and LF arteries in mdx and control mice. In LF arteries, sodium nitroprusside–induced dilation was significantly lower than in NF arteries in both mouse strains (in control mice, the maximal dilation was shifted from 98±3% to 38±3%, and the IC50 was shifted from 61±15 to 126±43 nmol/L [n=10, P<0.001]; in mdx mice, the maximal dilation was shifted from 96±2% to 31±6%, and the IC50 was shifted from 92±17 to 215±58 nmol/L [n=10, P<0.001]). Sodium nitroprusside–induced dilation was not significantly different in mdx and control mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study demonstrated a relationship between an endothelial defect in flow (shear stress) sensing in mesenteric arteries isolated from mdx mice and a defect in microvascular structural and functional adaptation to chronic changes in blood flow.
We used a model previously described in rats14,23 that allows for the study of resistance arteries submitted to different levels of blood flow in the same physiological conditions. Chronic increases and decreases in blood flow induce outward and inward arterial remodeling, respectively.14,15,23–25 These diameter changes allow the normalization of wall shear stress and are accompanied by a compensatory change in medial mass, which restores circumferential wall stress. In the mouse, we found that the structural adaptation of small resistance arteries to changes in blood flow was comparable to that described in rat small arteries14,18,23,24 and large compliance arteries.15,16 In addition, we found a correlation between the amplitude of the change in blood flow and the corresponding arterial remodeling.
In control mice, the chronic rise in blood flow led to an outward remodeling and to a normalization of the arterial wall shear stress, as previously shown in large15,16 and small14 arteries. In LF arteries, the remodeling was faster, and the reduction in blood flow resulted in an inward hypotrophic remodeling accompanied by the hyporeactivity of the arterial smooth muscle and endothelium, as previous described in the rat.14
In large arteries, flow-mediated vascular remodeling depends mainly on the capacity of the endothelium to generate vasodilator agents. In the carotid artery, inhibition of NO synthesis abolishes flow-induced remodeling.16 On the other hand, in resistance arteries, in a model similar to the one used in the present study, chronic NO synthesis inhibition failed to prevent flow-induced remodeling in the rat mesenteric artery.17 Nevertheless, eNOS expression increases in mesenteric resistance arteries chronically submitted to a high blood flow.18 This latter observation is in agreement with the findings of present study. Indeed, in HF arteries, we found a higher eNOS level and a stronger response to acute changes in flow (FMD). In addition, FMD was more sensitive to L-NAME in HF arteries than in NF arteries, suggesting that the involvement of NO was higher in the acute dilatory response to flow of HF arteries. Nevertheless, the fact that eNOS expression was increased in arteries submitted to HF does not exclude the possibility that NOS inhibition with L-NAME may fail to prevent the remodeling, as previously shown.17 In resistance arteries, flow induces not only the activation of NO synthesis but also that of other vasoactive agents.8,12,22 Thus, the exact role of NO in flow-induced remodeling in resistance arteries remains to be clarified. Indeed, NO might be one factor among others involved in the remodeling process in resistance arteries. Interestingly, NO can also be produced by skeletal muscle cells, which contain the neuronal isoform of NOS (nNOS). This production is decreased in mdx mice and patients with Duchenne muscular dystrophy, thus possibly contributing to lower the dilatory influence of the skeletal muscles on blood vessels.26–29 In arteries, nNOS may also play a role in situations such as hypertension in the rat.30 Nevertheless, we did not find nNOS or the inducible form of the enzyme in mesenteric arteries isolated from control or mdx mice (authors’ unpublished data, 2002).
In mdx mice, ligation of the mesenteric arteries did not produce an increase in blood flow (in the HF artery) as high as that in control mice. This might be due to the lower responsiveness of the arteries to flow.4 Nevertheless, it was possible to produce different groups of mice with increasing levels of flow in the HF arteries. This allowed us to compare mdx and control mice with the same degree of change in flow. In the mdx mouse, a chronic increase in blood flow failed to induce an enlargement of mesenteric resistance arterial diameter. This was associated with an absence of increase in flow (shear stress)–mediated dilation and an absence of increase in eNOS expression in contrast to the findings in control mice. Thus, there was impairment of not only the acute flow stimulation of eNOS but also the activation of its expression by a chronic increase in flow. Nevertheless, this does not necessarily mean that the low NO-dependent dilation found in mdx mice causes the absence of remodeling. In a previous study,25 we found an increased remodeling in the carotid artery submitted to HF in mice lacking the gene for vimentin. In these mice, FMD in renal and mesenteric resistance arteries is reduced,9 as it is in mdx mice.4 Similarly, in mice lacking desmin,19,20 we found a lower vascular reactivity, including a low endothelial responsiveness to flow, associated with an exaggerated remodeling in response to HF, using the model described in the present study.19 All together, these results suggest dissociation between acute (FMD) and chronic (remodeling) responses to flow. Thus, the decrease in FMD, eNOS expression, and remodeling observed in the same artery (and all depending on shear stress activation of endothelial cells) might be independent. The defect due to the absence of dystrophin could be located upstream. This is in agreement with the location and the role of dystrophin in muscle cells, in which dystrophin and dystrophin-glycoprotein complex are located at the level of the plasma membrane.1
The limited remodeling occurring in mdx mice might be of importance in the pathophysiology of dystrophin-related myopathies, such as Duchenne muscular dystrophy. In situations such as ischemia, physical training, or during growth, an inappropriate vascular wall adaptation to an increasing need in blood flow might be deleterious and increase tissue damages. In addition, we found an exaggerated diameter reduction of the LF artery. This might be deleterious in ischemic tissues, inasmuch as arteries submitted to LF would decrease their diameter excessively, thus leading to an increase apoptosis in cells submitted to a low shear stress.31 In patients suffering from dystrophin-related myopathies, the occurrence of ischemia has been shown in skeletal and cardiac muscles.32–34 Nevertheless, it should be noted that the present study was performed in mesenteric arteries not necessarily representative of the arteries present in skeletal and cardiac muscles, although they share common features, especially in their responsiveness to shear stress.6–9
Thus, in mdx mice, chronic changes in blood flow were not associated with an appropriate structural and biochemical adaptation of resistance arteries. These findings might be important in the pathophysiology of dystrophin-related myopathies, although the present findings would need further confirmation in arteries located in skeletal and cardiac muscles, mainly affected in myopathies.
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Acknowledgments |
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This study was supported in part by a grant from the French Association Against Myopathies (Association France-Myopathies [AFM]), Paris, France. Dr Loufrani was a fellow of the AFM.
Received March 6, 2002; revision received July 3, 2002; accepted November 6, 2002.
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  J.-L. Balligand, O. Feron, and C. Dessy eNOS Activation by Physical Forces: From Short-Term Regulation of Contraction to Chronic Remodeling of Cardiovascular Tissues Physiol Rev, April 1, 2009; 89(2): 481 - 534. [Abstract] [Full Text] [PDF]
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 E. J. Belin de Chantemele, E. Vessieres, A.-L. Guihot, B. Toutain, M. Maquignau, L. Loufrani, and D. Henrion Type 2 diabetes severely impairs structural and functional adaptation of rat resistance arteries to chronic changes in blood flow Cardiovasc Res, March 1, 2009; 81(4): 788 - 796. [Abstract] [Full Text] [PDF]
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 E.J. Belin de Chantemele, K. Retailleau, F. Pinaud, E. Vessieres, A. Bocquet, A.L. Guihot, B. Lemaire, V. Domenga, C. Baufreton, L. Loufrani, et al. Notch3 Is a Major Regulator of Vascular Tone in Cerebral and Tail Resistance Arteries Arterioscler. Thromb. Vasc. Biol., December 1, 2008; 28(12): 2216 - 2224. [Abstract] [Full Text] [PDF]
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E. N.T.P. Bakker, H. L. Matlung, P. Bonta, C. J. de Vries, N. van Rooijen, and E. VanBavel Blood flow-dependent arterial remodelling is facilitated by inflammation but directed by vascular tone Cardiovasc Res, May 1, 2008; 78(2): 341 - 348. [Abstract] [Full Text] [PDF]
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O. Dumont, F. Pinaud, A.-L. Guihot, C. Baufreton, L. Loufrani, and D. Henrion Alteration in flow (shear stress)-induced remodelling in rat resistance arteries with aging: improvement by a treatment with hydralazine Cardiovasc Res, February 1, 2008; 77(3): 600 - 608. [Abstract] [Full Text] [PDF]
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 C. Yan, A. Huang, G. Kaley, and D. Sun Chronic high blood flow potentiates shear stress-induced release of NO in arteries of aged rats Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3105 - H3110. [Abstract] [Full Text] [PDF]
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 C. Bouvet, E. B. de Chantemele, A.-L. Guihot, E. Vessieres, A. Bocquet, O. Dumont, A. Jardel, L. Loufrani, P. Moreau, and D. Henrion Flow-Induced Remodeling in Resistance Arteries From Obese Zucker Rats Is Associated With Endothelial Dysfunction Hypertension, July 1, 2007; 50(1): 248 - 254. [Abstract] [Full Text] [PDF]
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A. Csiszar, N. Labinskyy, K. E. Smith, A. Rivera, E. N.T.P. Bakker, H. Jo, J. Gardner, Z. Orosz, and Z. Ungvari Downregulation of Bone Morphogenetic Protein 4 Expression in Coronary Arterial Endothelial Cells: Role of Shear Stress and the cAMP/Protein Kinase A Pathway Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 776 - 782. [Abstract] [Full Text] [PDF]
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O. Dumont, L. Loufrani, and D. Henrion Key Role of the NO-Pathway and Matrix Metalloprotease-9 in High Blood Flow-Induced Remodeling of Rat Resistance Arteries Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 317 - 324. [Abstract] [Full Text] [PDF]
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 S. Lehoux and B. I. Levy Collateral Artery Growth: Making the Most of What You Have Circ. Res., September 15, 2006; 99(6): 567 - 569. [Full Text] [PDF]
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A. Koller Flow-Dependent Remodeling of Small Arteries: The Stimuli and the Sensors Are (Still) in Question Circ. Res., July 7, 2006; 99(1): 6 - 9. [Full Text] [PDF]
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E. N.T.P. Bakker, A. Pistea, J. A.E. Spaan, T. Rolf, C. J. de Vries, N. van Rooijen, E. Candi, and E. VanBavel Flow-Dependent Remodeling of Small Arteries in Mice Deficient for Tissue-Type Transglutaminase: Possible Compensation by Macrophage-Derived Factor XIII Circ. Res., July 7, 2006; 99(1): 86 - 92. [Abstract] [Full Text] [PDF]
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J. G. R. De Mey, P. M. Schiffers, R. H. P. Hilgers, and M. M. W. Sanders Toward functional genomics of flow-induced outward remodeling of resistance arteries Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1022 - H1027. [Abstract] [Full Text] [PDF]
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E. A. Koop, M. F. B. G. Gebbink, T. E. Sweeney, M.-J. Mathy, H. F. G. Heijnen, J. A. E. Spaan, E. E. Voest, E. VanBavel, and S. L. M. Peters Impaired flow-induced dilation in mesenteric resistance arteries from receptor protein tyrosine phosphatase-{micro}-deficient mice Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1218 - H1223. [Abstract] [Full Text] [PDF]
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 S. Straino, A. Germani, A. Di Carlo, D. Porcelli, R. De Mori, A. Mangoni, M. Napolitano, F. Martelli, P. Biglioli, and M. C. Capogrossi Enhanced Arteriogenesis and Wound Repair in Dystrophin-Deficient mdx Mice Circulation, November 23, 2004; 110(21): 3341 - 3348. [Abstract] [Full Text] [PDF]
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 Y. van Hensbergen, H. J. Broxterman, S. Rana, P. J. van Diest, M. C. A. Duyndam, K. Hoekman, H. M. Pinedo, and E. Boven Reduced Growth, Increased Vascular Area, and Reduced Response to Cisplatin in CD13-Overexpressing Human Ovarian Cancer Xenografts Clin. Cancer Res., February 1, 2004; 10(3): 1180 - 1191. [Abstract] [Full Text] [PDF]
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