Chronic Increase In Blood Flow Research Articles

Dual Role of Thrombospondin-1 in Flow-Induced Remodeling.

(1) Background: Chronic increases in blood flow, as in cardiovascular diseases, induce outward arterial remodeling. Thrombospondin-1 (TSP-1) is known to interact with matrix proteins and immune cell-surface receptors, but its contribution to flow-mediated remodeling in the microcirculation remains unknown. (2) Methods: Mesenteric arteries were ligated in vivo to generate high- (HF) and normal-flow (NF) arteries in wild-type (WT) and TSP-1-deleted mice (TSP-1−/−). After 7 days, arteries were isolated and studied ex vivo. (3) Results: Chronic increases in blood flow induced outward remodeling in WT mice (increasing diameter from 221 ± 10 to 280 ± 10 µm with 75 mmHg intraluminal pressure) without significant effect in TSP-1−/− (296 ± 18 to 303 ± 14 µm), neutropenic or adoptive bone marrow transfer mice. Four days after ligature, pro inflammatory gene expression levels (CD68, Cox2, Gp91phox, p47phox and p22phox) increased in WT HF arteries but not in TSP-1−/− mice. Perivascular neutrophil accumulation at day 4 was significantly lower in TSP-1−/− than in WT mice. (4) Conclusions: TSP-1 origin is important; indeed, circulating TSP-1 participates in vasodilation, whereas both circulating and tissue TSP-1 are involved in arterial wall thickness and diameter expansion.

0259 : Neutrophil and thrombospondin-1 implications in flow-mediated remodeling of resistance arteries from mice

On vascular endothelium, shear stress produces vasorelaxation and outward arterial remodeling. A chronic increase in blood flow induces arterial diameter expansion (normalizing shear stress), and is associated with a compensatory hypertrophy to normalize wall strain. This remodeling is due to Inflammation and nitric oxide (NO) production in resistance arteries. A large number of studies have demonstrated that Thrombospondin-1 (TSP1), a homotrimeric glycoprotein, can have an inhibitory action on the NO pathway and a positive effect on inflammation in vitro . Nevertheless, the role of TSP1 on remodeling is poorly understood. We hypothesized that TSP1 is able to participate in this outward arterial remodeling and hypertrophy by immune cells recruitment. We investigated this remodeling in mesenteric resistance arteries of WT or TSP1-KO mice aged to 12-16 weeks were used. An IgG2a isotype control mAb 2A3 or Ly6G-specific mAb 1A8 are used for neutrophil depletion by in vivo administration. Ligation of mesenteric resistance arteries of WT/TSP1- KO and IgG2a/neutrophil-depleted mice allowed modifying blood flow in vivo, thus exposing arteries to low (LF), normal (NF), or high flow (HF). After 7 days, arteries were isolated for in vitro study. Phenylephrine-mediated contraction and Acetylcholine-mediated relaxation were stronger in HF than in NF vessels on WT and IgG2a control mice. Any difference between HF or NF in TSP1-KO and neutrophil-depleted mice were found. Furthermore, passive diameter analysis revealed a higher diameter in HF than NF in WT and IgG2a mice. These differences are lost in TSP1-KO and neutrophil-depleted mice. These results suggest that TSP1 are essential for remodeling in mesenteric arteries by promoting neutrophils recruitment. The author hereby declares no conflict of interest

Resveratrol Improved Flow-Mediated Outward Arterial Remodeling in Ovariectomized Rats with Hypertrophic Effect at High Dose.

ObjectivesChronic increases in blood flow in resistance arteries induce outward remodeling associated with increased wall thickness and endothelium-mediated dilatation. This remodeling is essential for collateral arteries growth following occlusion of a large artery. As estrogens have a major role in this remodeling, we hypothesized that resveratrol, described as possessing phytoestrogen properties, could improve remodeling in ovariectomized rats.MethodsBlood flow was increased in vivo in mesenteric arteries after ligation of adjacent arteries in 3-month old ovariectomized rats treated with resveratrol (5 or 37.5 mg/kg per day: RESV5 or RESV37.5) or vehicle. After 2 weeks arterial structure and function were measured in vitro in high flow (HF) and normal flow (NF) arteries isolated from each rat.ResultsArterial diameter was greater in HF than in NF arteries in ovariectomized rats treated with RESV5 or RESV37.5, not in vehicle-treated rats. In mice lacking estrogen receptor alpha diameter was equivalent in HF and NF arteries whereas in mice treated with RESV5 diameter was greater in HF than in NF vessels. A compensatory increase in wall thickness and a greater phenylephrine-mediated contraction were observed in HF arteries. This was more pronounced in HF arteries from RESV37.5-treated rats. ERK1/2 phosphorylation, involved in hypertrophy and contraction, were higher in RESV37.5-treated rats than in RESV5- and vehicle-treated rats. Endothelium-dependent relaxation was greater in HF than in NF arteries in RESV5-treated rats only. In HF arteries from RESV37.5-treated rats relaxation was increased by superoxide reduction and markers of oxidative stress (p67phox, GP91phox) were higher than in the 2 other groups.ConclusionResveratrol improved flow-mediated outward remodeling in ovariectomized rats thus providing a potential therapeutic tool in menopause-associated ischemic disorders. This effect seems independent of the estrogen receptor alpha. Nevertheless, caution should be taken with high doses inducing excessive contractility and hypertrophy in association with oxidative stress in HF arteries.

Estrogens are needed for the improvement in endothelium-mediated dilation induced by a chronic increase in blood flow in rat mesenteric arteries

Resistance arteries play a key role in the control of local blood flow. They undergo outward remodeling in response to a chronic increase in blood flow as seen in collateral artery growth in ischemic disorders. We have previously shown that mesenteric artery outward remodeling depends on the endothelial estrogen receptor alpha. As outward arterial remodeling is associated with improved endothelium-dependent dilation, we hypothesized that estrogens might also play a role in flow-mediated improvement of endothelium-dependent dilation.Local increase in blood flow in first order mesenteric arteries was obtained after ligation of adjacent arteries in three-month old ovariectomized female rats treated with 17-beta-estradiol (OVX+E2) or vehicle (OVX).After 2weeks, diameter was equivalent in high flow (HF) than in normal flow (NF) arteries with a greater wall to lumen ratio in HF vessels in OVX rats. Acetylcholine-mediated relaxation was lower in HF than in NF vessels. eNOS and caveolin-1 expression level was equivalent in HF and NF arteries.By contrast, arterial diameter was 30% greater in HF than in NF arteries and the wall to lumen ratio was not changed in OVX+E2 rats. Acetylcholine-mediated relaxation was higher in HF than in NF arteries. The expression level of eNOS was higher and that of caveolin-1 was lower in HF than in NF arteries.Acetylcholine (NO-dependent)-mediated relaxation was partly inhibited by the NO-synthesis blocker L-NAME in OVX rats whereas L-NAME blocked totally the relaxation in OVX+E2 rats. Endothelium-independent relaxation (sodium nitroprusside) was equivalent in OXV and OVX+E2 rats. Similarly, serotonin- and phenylephrine-mediated contractions were higher in HF than in NF arteries in both OVX and OVX+E2 rats in association with high ratio of phosphorylated ERK1/2 to ERK1/2.Thus, we demonstrated the essential role of endogenous E2 in flow-mediated improvement of endothelium (NO)-mediated dilatation in rat mesenteric arteries.

0042 : Chronic increase in blood flow in rat mesenteric resistance arteries improved endothelium (NO)-mediated dilation: essential role of estrogens

Resistance arteries (RA) have a key role in the control of local blood flow. They undergo outward expansive remodeling in response to a chronic increase in blood flow as seen in post-ischemic collateral arteries growth. This remodeling is associated with improved endothelium-dependent dilation. We hypothesized that estrogens play a role in flow-mediated improvement of endothelium-dependent dilation. Local increase in blood flow in one mesenteric artery was obtained local surgery in three-month old ovariectomized female rats treated or not with 17-b-estradiol (E2). Changes in arterial function and structure were measured after 2 weeks. After 2 weeks, arterial diameter increased in high flow (HF) compared to normal flow (NF) arteries in ovariectomized rats treated with E2, not in untreated rats. Acetylcholine-mediated relaxation was higher in HF than in NF arteries in control and OVX rats treated with E2. In untreated rats, the relaxation was lower in HF than in NF vessels. eNOS expression level was higher in HF than in NF vessels in E2-treated rats only. Acetylcholine-mediated relaxation was fully dependent on the production of NO in E2-treated rats (total inhibition by the NO-synthesis blocker L-NAME). In untreated OVX rats L-NAME blocked only partly the relaxation. Endothelium-independent relaxation (sodium nitroprusside) was not affect by OVX or by E2. Serotoninand phenylephrine-mediated contraction was higher in HF than in NF arteries in both treated and untreated OVX rats. Thus, we demonstrated the essential role of endogenous E2 in flowmediated improvement of endothelium (NO)-mediated dilation in mesenteric resistance arteries.

0223 : Dual effect of resveratrol on flow-mediated outward hypertrophic remodeling in ovariectomized rat mesenteric resistance arteries

Resistance arteries control local blood flow. Chronic increases in blood flow in RA occur in growth, pregnancy, exercising as well as to compensate ischemia and induce outward hypertrophic remodeling associated with improved endothelium dilation. As estrogens have a key role in flow-mediated remodeling, we hypothesized that resveratrol, suggested to act as phytoestrogen, may improve flow-mediated remodeling in ovariectomized rats. Blood flow was increased in vivo in one mesenteric resistance artery without other changes in pressure or circulating factors in three-month old ovariectomized female rats treated with resveratrol (5 or 37.5mg/kg per day in osmotic minipumps: RESV5 or RESV37.5) or solvent (DMSO). After 2 weeks arterial structure and function were measured in vitro. Arterial diameter increased in high flow (HF) compared to normal flow (NF) arteries in ovariectomized rats treated with RESV5 or RESV37.5, not in control rats. Hypertrophy in HF arteries occurred in the 3 groups but was greater in RESV37.5-treated rats so that wall / lumen ratio was elevated in this group. ERK1/2 activation, involved in flow-mediated hypertrophy was greater in RESV37.5-treated rats than in RESV5 – and DMSO-treated rats. RESV5, not RESV37.5, improved L-NAME sensitive arterial relaxation. eNOS expression level was equivalent in HF and NF vessels in all groups animals. Markers of oxidative stress (p67phox, GP91phox) were greater in arteries of RESV37.5-treated rats than in RESV5 – and solvent-treated rats. They were also higher in HF arteries in RESV37.5-treated rats. Thus, although resveratrol improved flow-mediated outward hypertrophic remodeling in OVX rats, the high dose induced oxidative stress and hypertrophy.

Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries.

In resistance arteries, a chronic increase in blood flow induces hypertrophic outward remodeling. This flow-mediated remodeling (FMR) is absent in male rats aged 10 mo and more. As FMR depends on estrogens in 3-mo-old female rats, we hypothesized that it might be preserved in 12-mo-old female rats. Blood flow was increased in vivo in mesenteric resistance arteries after ligation of the side arteries in 3- and 12-mo-old male and female rats. After 2 wk, high-flow (HF) and normal-flow (NF) arteries were isolated for in vitro analysis. Arterial diameter and cross-sectional area increased in HF arteries compared with NF arteries in 3-mo-old male and female rats. In 12-mo-old rats, diameter increased only in female rats. Endothelial nitric oxide synthase expression and endothelium-mediated relaxation were higher in HF arteries than in NF arteries in all groups. ERK1/2 phosphorylation, NADPH oxidase subunit expression levels, and arterial contractility to KCl and to phenylephrine were greater in HF vessels than in NF vessels in 12-mo-old male rats only. Ovariectomy in 12-mo-old female rats induced a similar pattern with an increased contractility without diameter increase in HF arteries. Treatment of 12-mo-old male rats and ovariectomized female rats with hydralazine, the antioxidant tempol, or the angiotensin II type 1 receptor blocker candesartan restored HF remodeling and normalized arterial contractility in HF vessels. Thus, we found that FMR of resistance arteries remains efficient in 12-mo-old female rats compared with age-matched male rats. A balance between estrogens and vascular contractility might preserve FMR in mature female rats.

AGEs breaking and antioxidant treatment improves endothelium-dependent dilation without effect on flow-mediated remodeling of resistance arteries in old Zucker diabetic rats

BackgroundA chronic increase in blood flow in resistance arteries is associated with increased lumen diameter (outward remodeling) and improved endothelium (NO)-mediated relaxation. Flow-mediated remodeling of resistance arteries is essential for revascularization in ischemic diseases. Nevertheless, it is impaired in 12 to 24-month old rats and in young Zucker Diabetic Fatty (ZDF) rats due to advanced glycation end products (AGEs) and oxidative stress. As type 2 diabetes occurs preferentially in older subjects we investigated flow-mediated remodeling and the effect of the AGEs breaker ALT-711 associated or not to the antioxidant TEMPOL in one-year old lean (LZ) and ZDF rats.MethodsMesenteric resistance arteries were exposed to high (HF) or normal blood flow (NF) in vivo. They were collected after 2 weeks for in vitro analysis.ResultsIn LZ rats, diameter expansion did not occur despite a significant increase in blood flow in HF arteries. Nevertheless, endothelium-mediated relaxation was higher in HF than in NF arteries. ALT-711, alone or in combination with TEMPOL, restored outward remodeling in HF arteries in association with AGEs reduction. TEMPOL alone had no effect. ALT-711, TEMPOL or the combination of the 2 drugs did not significantly affect endothelium-mediated relaxation in HF and NF arteries.In ZDF rats, diameter did not increase despite the increase in blood flow and endothelium-mediated relaxation was further decreased in HF arteries in association with AGEs accumulation and excessive oxidative stress. In both NF and HF arteries, endothelium-mediated relaxation was lower in ZDF than in LZ rats. ALT-711, TEMPOL or their combination did not improve remodeling (diameter equivalent in HF and NF arteries). In parallel, they did not reduce AGEs level and did not improve MMPs activity. Nevertheless, ALT-711 and TEMPOL partly improved endothelium-mediated relaxation through a reduction of oxidative stress and the association of ALT-711 and TEMPOL fully restored relaxation to the level found in LZ rats.ConclusionsALT-711 did not improve outward remodeling in mature ZDF rats but it reduced oxidative stress and consequently improved endothelium-dependent relaxation. In mature LZ rats, ALT-711 improved outward remodeling and reduced AGEs level. Consequently, AGEs breaking is differently useful in ageing whether it is associated with diabetes or not.

Pulmonary vascular remodeling in broiler and Leghorn chickens after unilateral pulmonary artery occlusion

Morphological and physiological responses to unilateral pulmonary artery occlusion (PAO) were evaluated in male broiler (B) and Leghorn (L) chickens. All birds were fed a diet containing 3,200 kcal of ME/kg of feed and 23% CP. Broilers (18-21 d old; 507 ± 40 g of BW) and L (61-64 d old, 861 ± 87 g of BW) had surgical PAO (n = 40 each strain) or were sham-operated (SHAM; n = 40 each strain). Hematocrit (%, Hc), relative lung weight (wet right + left lung weight/BW × 100), right ventricle to total ventricle weight ratio (RV/TV), and resistance pulmonary arterioles (RPA) thickness were measured in 6 chickens per group one day presurgery, and at 7 and 14 d postsurgery. Data were analyzed using one-way ANOVA. Relative lung weight was higher in L-chickens than in B-chickens at all sampling times. There were no differences in Hc between B and L presurgery, but at d 7 and 14, L-PAO chickens had the highest Hc (35 ± 1.4 and 40 ± 1.9, respectively); the B-SHAM had a lower Hc (28 ± 1.2, and 29 ± 1.0) than the L-SHAM (32 ± 1.2 and 34 ± 1.1) and the B-PAO (32 ± 1.2 and 34 ± 2.0) chickens, with no differences between L-SHAM and B-PAO. The RV/TV ratio was highest in the B-PAO at d 7 and d 14, with no differences among the other groups. The B-PAO chickens had the thickest RPA at 7 d and 14 d postsurgery than the rest of the groups, whereas B had thicker RPA than L at presurgery. Broilers had a lower ventilation capacity than L, and after PAO they developed right ventricular hypertrophy and small arteriole remodeling, whereas the L-PAO showed a higher degree of hypoxemia (high Hct), but without changes in RV/TV ratios or small arterial remodeling, suggesting that L-chickens had a better pulmonary arterial vasodilation even after chronic increases in blood flow through a single lung.

Cyclooxygenase-2 preserves flow-mediated remodelling in old obese Zucker rat mesenteric arteries

Resistance arteries have a key role in the control of local blood flow and pressure, and chronic increases in blood flow induce endothelium-dependent outward hypertrophic remodelling. The incidence of metabolic syndrome increases with age, and the combination of these two risk factors impairs endothelium integrity, in part through an inflammatory process. We hypothesized that cyclooxygenase-2 (COX2) would affect remodelling in 12-month-old obese rats compared with young rats. Mesenteric arteries of obese and lean Zucker rats were alternatively ligated to generate high flow (HF) in the median artery. After 21 days, arteries were isolated for in vitro analysis. After 21 days, outward hypertrophic remodelling occurred in HF arteries in obese (498 +/- 20 vs. 443 +/- 18 mum intraluminal diameter in normal flow (NF) arteries, P < 0.01), but not in lean rats (454 +/- 17 vs. 432 +/- 14, NS; n = 12 per group). Endothelium-dependent (acetylcholine)-mediated relaxation (AMR) was lower in obese than in lean rats. AMR was reduced by NO-synthase blockade in all groups, and eNOS expression was higher in HF than in NF arteries without difference between lean and obese rats. Indomethacin further reduced AMR in HF arteries from obese rats only. Obesity increased COX2 immunostaining in mesenteric arteries. Acute COX2 inhibition (NS398) significantly reduced AMR in HF arteries from obese rats only, suggesting production of vasodilator prostanoid(s). In obese rats chronically treated with the COX2 inhibitor celecoxib, outward remodelling did not occur in HF arteries and AMR was improved without reaching the level found in lean rats. COX2 preserved in part flow-mediated arterial remodelling in old obese rats. Nevertheless, this effect was not sufficient to keep endothelium-dependent relaxation to the level obtained in lean rats.

Role of Angiotensin II in the Remodeling Induced by a Chronic Increase in Flow in Rat Mesenteric Resistance Arteries

Angiotensin II is a potent growth factor involved in arterial wall homeostasis. In resistance arteries, chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy. Nevertheless, the role of angiotensin II in this remodeling is unknown. We investigated the effect of blocking angiotensin II production or receptor activation on flow-induced remodeling of mesenteric resistance arteries. Arteries were ligated in vivo to generate high-flow arteries compared with normal flow (control) vessels located at a distance. Arteries were isolated after 1 week for in vitro analysis. Arterial diameter, media surface, endothelial NO synthase expression, superoxide production, and extracellular signal-regulated kinase 1/2 phosphorylation were higher in high-flow than in control arteries. Angiotensin-converting enzyme inhibition (perindopril) and angiotensin II type 1 receptor blockade (candesartan) prevented arterial wall hypertrophy without affecting diameter enlargement. The nonselective vasodilator hydralazine had no effect on remodeling. Although perindopril and candesartan increased endothelial NO synthase expression in high-flow arteries, hypertrophy remained in rats treated with N(G)-nitro-l-arginine methyl ester and mice lacking endothelial NO synthase. Perindopril and candesartan reduced oxidative stress in high-flow arteries, but superoxide scavenging did not prevent hypertrophy. Both Tempol and the absence of endothelial NO synthase prevented the rise in diameter in high-flow vessels. Extracellular signal-regulated kinase 1/2 activation in high-flow arteries was prevented by perindopril and candesartan and not by hydralazine. Extracellular signal-regulated kinase 1/2 inhibition in vivo (U0126) prevented hypertrophy in high-flow arteries. Thus, a chronic rise in blood flow in resistance arteries induces a diameter enlargement involving NO and superoxide, whereas hypertrophy was associated with extracellular signal-regulated kinase 1/2 activation by angiotensin II.

Reactive Oxygen Species Are Necessary for High Flow (Shear Stress)‐induced Diameter Enlargement of Rat Resistance Arteries

Chronic increases in blood flow induce remodeling associated with increases in diameter and endothelium-mediated dilation. Remodeling requires cell growth and migration, which may involve reactive oxygen species (ROS). Nevertheless, the role of ROS in flow-mediated remodeling in resistance arteries is not known. Rat mesenteric resistance arteries (MRAs) were exposed to high flow (HF) by sequentially ligating second-order MRAs in vivo. After three weeks, arteries were collected for structural, pharmacological, and biochemical analysis. In HF arteries, luminal diameter (431+/-12 to 553+/-14 microm; n=10), endothelium (acetylcholine)-mediated vasodilatation (61+/-6 to 77+/-6% relaxation) and NAD(P)H subunit (gp91phox and p67phox) expression levels, and ROS (dihydroethydine microphotography) and peroxynitrite (3-nitro-tyrosine) production were higher than in normal flow arteries. Acute ROS scavenging with tempol improved acetylcholine-dependent relaxation (92+/-4% relaxation), confirming that ROS are produced in HF arteries. Chronic treatment with tempol prevented the increase in diameter, reduced ROS and peroxynitrite production, and improved endothelium-mediated relaxation in HF arteries. Thus, ROS and NO were involved in HF-induced diameter enlargement, possibly through the formation of peroxynitrite, while ROS reduced the increase in endothelium-dependent relaxation. ROS production is necessary for flow-mediated diameter enlargement of resistance arteries. However, ROS counteract, in part, the associated improvement in endothelium-mediated relaxation.

Type 2 diabetes severely impairs structural and functional adaptation of rat resistance arteries to chronic changes in blood flow

Endothelial dysfunction in resistance arteries (RAs) leads to end-organ damage in type 2 diabetes. Remodelling of RAs in response to chronic increases in blood flow depends on the integrity of the endothelium. Since type 2 diabetes impairs endothelial sensitivity to flow and increases oxidative stress, we hypothesized that flow-induced remodelling in RAs would be impaired in diabetes. Thus, we studied the structural and functional adaptation of RAs from Zucker diabetic fatty (ZDF) and lean Zucker (LZ) rats to chronic changes in flow. Mesenteric RAs were alternatively ligated so that one artery was submitted to high flow (HF) and compared with normal-flow (NF) arteries located at distance. After 3 weeks, arteries were studied in vitro (n = 10 rats per group). Arterial diameter (468 vs. 394 +/- 8 microm) and endothelial (acetylcholine)-dependent dilation (91 +/- 8 vs. 75 +/- 6% dilation) were higher in HF than in NF arteries in LZ rats. In ZDF rats, diameter (396 +/- 9 vs. 440 +/- 17 microm) and acetylcholine-mediated dilation (42 +/- 8 vs. 75 +/- 7%) were lower in HF than in NF arteries. Nevertheless, endothelial NO synthase and NADP(H) oxidase subunits (gp91, p67) expression level and superoxide production (dihydroethidium staining) were higher in HF than in NF arteries in both strains, suggesting an efficient flow-sensing process in ZDF rats. In ZDF rats, basal oxidative stress was higher compared with LZ rats: dihydroethidium staining was higher in NF and HF arteries from ZDF rats, and acetylcholine-mediated dilation was improved by an acute antioxidant (tempol) in NF and HF arteries from ZDF rats. Thus, superoxide overproduction in ZDF rats impaired NO-dependent dilation and HF remodelling. Indeed, a chronic treatment with tempol increased HF artery diameter and endothelium-dependent dilation in ZDF rats. In type 2 diabetic rats, a chronic increase in blood flow failed to induce outward remodelling and to improve endothelium-dependent dilation, mainly because of superoxide overproduction.

Femoral artery diameter and arteriogenic cytokines in healthy women

Animal studies have identified monocyte chemoattractive protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) as critical mediators of arterial diameter enlargement in response to chronic increases in blood flow (arteriogenesis). Furthermore, cellular studies have shown that the shear stresses resulting from increased blood flow stimulate synthesis of MCP-1, which in turn stimulates synthesis of VEGF. The purpose of this study was to determine if these mechanisms are evident in healthy women. Resting femoral artery diameter and blood flow, lean leg mass, MCP-1 and VEGF concentrations, and aerobic capacity were measured in 34 healthy women along with plasma concentrations of lipids associated with cardiovascular disease risk. Femoral artery diameter was independently related to metabolically active (lean) leg mass ( b = 0.41, P = 0.008) and aerobic capacity ( b = 0.45, P = 0.004). Plasma MCP-1 correlated negatively with the ratio of femoral artery diameter to lean leg mass ( b = − 0.42, P = 0.009) and positively with serum triglycerides ( b = 0.46, P = 0.005). Plasma VEGF exhibited similar correlations and strongly correlated with MCP-1 ( R = 0.92, P < 0.0001). The results indicate that circulating MCP-1 and VEGF concentrations are associated with both arteriogenic and atherogenic stimuli in healthy women.

Alteration in flow (shear stress)-induced remodelling in rat resistance arteries with aging: improvement by a treatment with hydralazine

The link between aging and vascular diseases remains unclear, especially in resistance arteries. As a decreased vasodilator capacity of the endothelium is usually described in aging, we hypothesized that arteriolar remodelling in response to a chronic increase in blood flow might be altered. In addition, we tested the capacity of a vasodilator treatment with hydralazine to restore remodelling, as we have previously shown that hydralazine has a potent effect on the process. Mesenteric resistance arteries (350 microm diameter) from 3- and 24-month-old rats were exposed to high blood flow (HF) and normal blood flow (NF), for 2 weeks by sequential ligating second-order arteries in vivo. In HF arteries, diameter increased by 21% when intraluminal pressure was 100 mmHg, in association with a rise in superoxide production in young rats. On the other hand, both diameter and superoxide levels failed to increase in old rats. Hydralazine restored HF-induced remodelling in old rats in association with an increased superoxide production and a decreased superoxide dismutase (SOD) expression. The SOD-mimetic 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (TEMPOL) prevented the effect of hydralazine on the arterial diameter. In old rats, hydralazine increased the arterial diameter in HF arteries without increasing eNOS expression. Furthermore, hydralazine also restored HF remodelling in eNOS knockout mice. Thus, flow remodelling in resistance arteries failed to occur in aging but it could be restored by hydralazine via a reactive oxygen species-dependent mechanism. These findings may have serious pathophysiological consequences in situations requiring flow-dependent remodelling such as ischaemic and metabolic diseases, more frequent in the elderly.

Resistance arteries remodeling induced in vivo by a chronic increase in blood flow is severely altered in type 2 diabetes

Resistance arteries remodeling induced in vivo by a chronic increase in blood flow is severely altered in type 2 diabetes

Involvement of NO and MMPs in microvascular remodeling induced by chronic changes in blood flow

Although the role of NO and MMPs in flow (shear stress)-induced remodeling in large compliance arteries is clearly demonstrated, in resistance arteries the mechanism of this remodeling remains mainly unknown and controversial. We submitted mesenteric resistance arteries to chronic increases in blood flow by ligating second order arteries. Arteries submitted to high (HF) were compared to normal flow arteries (NF). Rats were treated with the NO synthase inhibitor L-NAME (60mg/kg) plus the angiotensin converting enzyme inhibitor perindopril (6mg/kg), perindopril (6mg/kg), or the MMPs inhibitor doxycycline (40mg/kg). After 3 weeks, arteries were studied in vitro in an arteriograph. In control rats, diameter increased in HF (438±10.4 at 75 mmHg) compared to NF (340±13.6 at 75 mmHg). In order to get more insight in the mechanism involved in remodeling, we measured in HF and NF arteries, 4 or 14 days after ligation, eNOS expression and MMP-2 and -9 activity and expression using respectively western blot, in situ zymography and immunohistochemistry. Four days after ligation, eNOS expression and MMP activity increased in HF arteries. In addition, L-NAME plus perindopril (used to prevent L-NAME-induced rise in blood pressure) as well as the genetic absence of eNOS in mice, prevented HF remodeling. Perindopril alone did not affect HF remodeling. The role of MMPs in flow-remodeling was confirmed by the use of the MMPs inhibitor doxycycline, which blunted HF remodeling. We conclude that high flow-induced remodeling in resistance arteries involves eNOS overexpression and increased MMP activity, the production of NO and the activity of MMPs being central in this process.

Toward functional genomics of flow-induced outward remodeling of resistance arteries

In resistance-sized arteries, a chronic increase in blood flow leads to increases in arterial structural luminal diameter and arterial wall mass. In this review, we summarize recent evidence that outward remodeling of resistance arteries 1) can help maintain and restore tissue perfusion, 2) is not intimately related to flow-induced vasodilatation, 3) involves transient dedifferentiation and turnover of arterial smooth muscle cells, and 4) is preceded by increased expression of matricellular proteins, which have been shown to promote disassembly of focal adhesion sites. Studies of experimental and physiological resistance artery remodeling involving differential gene expression analyses and the use of knockout and transgenic mouse models can help unravel the mechanisms of outward remodeling.

Radial artery remodeling in response to shear stress increase within arteriovenous fistula for hemodialysis access.

It is known that changes in blood flow induce vascular remodeling and that shear stress, the tractive force acting on the vessel wall due to blood flowing, influences endothelial cell function. The aim of the present study was to investigate the relation between changes in pulsatile shear forces and arterial remodeling in response to chronic elevation in blood flow within the radial artery. The authors studied vessel diameter, flow rate, and shear stress in the radial artery of uremic patients before and after surgical creation of a native arteriovenous fistula for hemodialysis access. For this purpose, the authors used echo-color-Doppler ultrasound to perform diameter and blood velocity measurements. Time-function blood flow rate and wall shear stress were calculated based on arterial diameter, center-line velocity wave-form, and blood viscosity, using a numerical method developed according to Womersley's theory for unsteady flow in tubes. The results confirmed that the radial artery diameter increases in response to a chronic increase in blood flow in uremic patients. Moreover, it seems that the radial artery dilates in such a way as to maintain the peak wall shear stress constant, suggesting that endothelial cells sense the maximum rather than the time-averaged wall shear stress. This finding may lead to further understanding of the mechanisms responsible for endothelial response to physical stimulation by flowing blood.

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 μl/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 μm 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.