OBJECTIVE:Both innate and adaptive immune systems may contribute to the pathogenesis of cardiovascular disease and vascular remodeling through inflammation and oxidative stress. Particularly, the ...balance between Th1 effector lymphocytes (producing interferon-γ) and T regulatory (Treg) lymphocytes, which elicit an anti-inflammatory activity, may be crucial for blood pressure elevation and organ damage development, at least in experimental models. In particular, Tregs have been previously demonstrated to inversely correlate with subcutaneous small resistance artery media to lumen ratio (M/L) and retinal arteriole wall to lumen ratio (W/L) (unpublished data). Therefore, we evaluate the possible relationship between Th1 or Treg lymphocytes and microvascular oxidative stress.
DESIGN AND METHOD:We enrolled 11 normotensive subjects and 4 hypertensive patients undergoing an election surgical intervention. No sign of local or systemic inflammation was present in any subjects or patients. All patients underwent a biopsy of subcutaneous fat during surgery. A peripheral blood sample was obtained before surgery for assessment of T lymphocyte populations. Lymphocyte phenotype was evaluated by flow cytometry after 5 hour in vitro activation in order to assess Th1 lymphocytes. Superoxide anion production, as index of oxidative stress, was evaluated in the bioptic tissue by florescent dye dihydroethidium and quantified using an image analyzer.
RESULTS:Results are summarized in the Table (RTErecent thymus emigrant; EMeffector memory).(Figure is included in full-text article.)A significant positive correlation was observed between Th1 lymphocytes and superoxide anion production in subcutaneous microvessels. Additionally, a significant inverse correlation was observed between microvascular free radical production and Total Treg, RTE and EM Tregs.
CONCLUSIONS:Our data suggest that Treg lymphocytes may be protective against microvascular damage, probably because of their anti-oxidant properties confirming an involvement of adaptive immune system on microvascular damage.
OBJECTIVE:It was proposed that early vascular ageing may be an important mechanism of vascular damage in large conductance arteries. However it is not known whether aging may also affect small ...resistance artery morphology.
DESIGN AND METHOD:For this reason, we investigated 100 patients with essential hypertension. Secondary forms of hypertension were excluded according to standard clinical evaluations and biochemical or instrumental assessments. In all patients, an evaluation of small resistance arteries morphology was performed by a wire micromyographic approach (Mulvanyʼs technique). A small amount of subcutaneous tissue was obtained by local biopsy or during election surgery and subcutaneous small resistance arteries were dissected and mounted on a myograph; the media to lumen ratio (M/L) was then measured.
RESULTS:The age range of our population was 22–81 years, with a mean value of 57 ± 12 years; 14% of them were current smokers, 32% had alterations in lipid patterns, none of them had diabetes mellitus, 58 were males and average blood pressure values were 156/95 ± 19/12 mmHg.We found a significant correlation between M/L and age (r = 0.30, p = 0.002)the statistical significance of the correlation persisted after correction for counfounding variables (gender, serum cholesterol, smoking status, serum glucose, systolic or diastolic blood pressure values). A statistically significant inverse correlation was also observed between internal diameter and age (r = -0.20, p = 0.046), while the correlation between age and media thickness did not reach statistical significance (r = 0.09, p = 0.37).
CONCLUSIONS:Our data suggest that aging may affect microvascular structure in hypertensive patients. It is also possible that hypertension may anticipate the effects of physiological aging, and this should be explored in a relatively large population of normotensive subjects.
OBJECTIVE:It has been previously demonstrated that inflammation in adipose tissue may be implicated in vascular dysfunction (Circulation 2009; 119(12):1661–1670). A senescence-accelerated prone mouse ...(SAMP8) is a model of age-related cognitive decline and vascular dysfunction. Several studies demonstrated that SAMP8 suffers from increased oxidative stress and that accelerated senescence was associated with decreased eNOS and nNOS and increased oxygen radicals synthesis. Aim of the study was to investigate functional responses of small mesenteric arteries in a senescence-accelerated prone mouse (SAMP8) before and after chronic treatment with melatonin.(Figure is included in full-text article.)
DESIGN AND METHOD:We investigated 7 SAMP8 and 7 SAMR1 normal controls. Mesenteric small resistance arteries were dissected and mounted on a wire myograph, according to Mulvany-Halpern technique (internal diameter about 200 μm). A concentration-response to norepinephrine (NE, from 10–9 to 10-5 Mol/l) was evaluated in vessels with intact prerivascular fat tissue (WF) and in vessels in which perivascular fat tissue was removed (NoF). Investigations were repeated in 7 SAMP8 and 7 SAMR1 after 54 weeks of chronic treatment with melatonin, an endogenous hormone with antioxidant and vasculoprotective properties.
RESULTS:In SAMR1 control mice anticontractile effect of perivascular fat was present (WF vs. NoFANOVA p = 0.04), while in aging SAMP8 mice the effect was less pronounced (WF vs. NoFANOVA p = NS) (see figure). Long-term treatment with melatonin had no effect in SAMR1 either in WF or NoF vessels, while it decreased the contractile response to norepinephrine in noF vessels of SAMP8 (ANOVA p < 0.001); the effect of melatonin treatment in WF vessels was not statistically significant.
CONCLUSIONS:The anticontractile effect of perivascular fat is impaired in a senescence-accelerated prone mouse, compared with controls. A long-term treatment with melatonin seems to decrease contractile responses to norepinephrine in NOF mesenteric small arteries of SAMP8, thus restoring an anticontractile effect, probably through antioxidant mechanisms.
Objective
It has been previously demonstrated that T lymphocytes may be involved in the development of hypertension and microvascular remodeling, and that circulating T effector lymphocytes may be ...increased in hypertension. In particular, Th1 and Th17 lymphocytes may contribute to the progression of hypertension and microvascular damage while TREG lymphocytes seem to be protective. However, no data is available about patients with severe obesity, in which pronounced microvascular alterations were observed.
Methods
We have investigated 32 severely obese patients undergoing bariatric surgery, 24 normotensive lean subjects and 11 hypertensive lean subjects undergoing an election surgical intervention. No sign of local or systemic inflammation was present in any subject or patient. A peripheral blood sample was obtained before surgery for assessment of CD4+ T lymphocyte subpopulations. Lymphocyte phenotype was evaluated by flow cytometry after 5 hour in vitro activation in order to assess T-effector and T-regulatory (TREG) lymphocytes. Subsets of TREGS were defined as follows: −TREGS recent thymic emigrants (RTE), directly derived from thymus: CD31+; −TREGS naïve: CCR7+CD45RA+; −TREGS central memory (CM): CCR7+CD45RA−; −TREGS effector memory (EM): CCR7−CD45RA−; −TREGS terminal differentiated effector memory (TDEM): CCR7−CD45RA+.
Results
The results are summarized in the Table (*p < 0.05, **p < 0.01, ***p < 0.001 vs. lean normotensives; #p < 0.05, ##p < 0.01, ###p < 0.001 vs. lean hypertensives). A marked reduction of several TREG subpopulations was observed in obese patients compared with controls, together with an increased in some T-effector cells.
Lean normotensives
Lean hypertensives
Obese patients
TREGs (%)
4.11 ± 1.60
4.64 ± 1.66
2.69 ± 1.81**##
TREGs (abs number)
45.4 ± 24.3
45.4 ± 23.8
27.3 ± 21.1**#
TREGs naíve (%)
22.1 ± 10.1
18.1 ± 13.1
13.34 ± 12.9**
TREGs naíve (abs number)
10.6 ± 7.75
9.71 ± 8.87
3.87 ± 5.28***##
TREG CM (%)
32.3 ± 13.8
32.8 ± 17.8
22.7 ± 15.2*#
TREGs CM (abs number)
14.7 ± 10.2
14.2 ± 9.08
6.10 ± 8.08***##
CD4+ EM (%)
24.4 ± 9.96
26.8 ± 12.5
34.1 ± 13.3**
CD161+CD28+ (%)
86.2 ± 28.5
94.9 ± 5.63
97.2 ± 5.39*
Conclusion
TREG lymphocytes are clearly reduced in severely obese patients, possibly contributing to the development of marked microvascular alterations previously observed in such a population.
Objective
: A relevant biological role of circulating endothelial progenitor cells (EPC) was recently demonstrated. EPC are generated in the bone marrow, and interact with damaged endothelium, ...restoring the integrity of the monolayer. Therefore, aim of the present study was to evaluate EPC in the blood of patients with untreated Graves’ hyperthyroidism (GD), in whom an increased oxidative stress was observed.
Design and methods
: Twenty-three patients with untreated active GD and 18 matched normal controls (NC) were included in the study. Circulating EPC were isolated from peripheral blood. Mononuclear cells were cultured with endothelial basal medium supplemented with EGM SingleQuots, and were identified by positive double staining after 7 days in culture. Circulating levels of C reactive protein, total antioxidant power, interleukin (IL)-6, IL-18, monocyte chemoattractant protein-1, tumor necrosis facotr-α, soluble vascular cell adhesion molecule (VCAM) and intracellular adhesion molecule were evaluated by enzyme-linked immunosorbent assay kit. EPC number was also evaluated in a subgroup of GD patients after restoration of euthyroidism.
Results
: Systolic blood pressure resulted increased in GD patients compared with control subjects whereas diastolic blood pressure was not significantly different. Patients with GD showed an increase in circulating levels of IL-18 and VCAM-1 and a reduction of total antioxidant power (
p
<0.05) compared to NC. Moreover, a reduced number of EPC was observed in patients with GD compared to NC (
p
<0.05) which turned to NC values after restoring euthyroidism.
Conclusion
: Patients with GD showed a reduction in the physiological protective mechanisms against endothelial damage, probably induced by increased inflammation and oxidative stress.
OBJECTIVEA relevant biological role of circulating endothelial progenitor cells (EPC) was recently demonstrated. EPC are generated in the bone marrow, and interact with damaged endothelium, restoring ...the integrity of the monolayer. Therefore, aim of the present study was to evaluate EPC in the blood of patients with untreated Graves' hyperthyroidism (GD), in whom an increased oxidative stress was observed. DESIGN AND METHODSTwenty-three patients with untreated active GD and 18 matched normal controls (NC) were included in the study. Circulating EPC were isolated from peripheral blood. Mononuclear cells were cultured with endothelial basal medium supplemented with EGM SingleQuots, and were identified by positive double staining after 7 days in culture. Circulating levels of C reactive protein, total antioxidant power, interleukin (IL)-6, IL- 18, monocyte chemoattractant protein-1, tumor necrosis facotr- α, soluble vascular cell adhesion molecule (VCAM) and intracellular adhesion molecule were evaluated by enzymelinked immunosorbent assay kit. EPC number was also evaluated in a subgroup of GD patients after restoration of euthyroidism. RESULTSSystolic blood pressure resulted increased in GD patients compared with control subjects whereas diastolic blood pressure was not significantly different. Patients with GD showed an increase in circulating levels of IL-18 and VCAM-1 and a reduction of total antioxidant power (p<0.05) compared to NC. Moreover, a reduced number of EPC was observed in patients with GD compared to NC (p<0.05) which turned to NC values after restoring euthyroidism. CONCLUSIONPatients with GD showed a reduction in the physiological protective mechanisms against endothelial damage, probably induced by increased inflammation and oxidative stress.
The presence of structural alterations in the microcirculation may be considered an important mechanism of organ damage; however, it is not currently known whether structural alterations of small ...arteries may predict fatal and nonfatal cardiovascular events.
One hundred twenty-eight patients were included in the present study. There were 59 patients with essential hypertension, 17 with pheochromocytoma, 20 with primary aldosteronism, 12 with renovascular hypertension, and 20 normotensive patients with non-insulin-dependent diabetes mellitus. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on an isometric myograph, and the tunica media-to-internal lumen ratio (M/L) was measured. The subjects were reevaluated after an average follow-up time of 5.4 years. Thirty-seven subjects had a documented fatal or nonfatal cardiovascular event (5.32 events/100 patients per year). In the subcutaneous small arteries of subjects with cardiovascular events, a smaller internal diameter and a clearly greater M/L was observed. Our subjects were subdivided according to the presence of an M/L greater or smaller than the mean and median values observed in the whole population (0.098) or mean value +2 SD of our normal subjects (0.11). Life-table analyses showed a significant difference in event-free survival between the subgroups. Cox's proportional hazard model, considering all known cardiovascular risk factors, indicated that only pulse pressure (P=0.009) and M/L (P<0.0001) were significantly associated with the occurrence of cardiovascular events.
Our results strongly indicate a relevant prognostic role of structural alterations in small resistance arteries of a high-risk population.
Background
The anticontractile effect of perivascular adipose tissue(P-VAT) is lost in obese patients due to adipocyte hypertrophy, leading to hypoxia, inflammation, and oxidative stress(Circulation ...2009; 119(12):1661–1670). We recently demonstrated that the property of PVAT, partially maintained in an animal model of genetic obesity, seems to be related to the activity of BK
CA
channels, since is selectively blocked by iberiotoxin. We aimed to investigate functional responses of small mesenteric arteries in an animal model of genetic obesity after chronic treatment with melatonin, an endogenous hormone with antioxidant and vasculoprotective properties.
Methods
Obese mice (
n
= 9) (B6.V-Lep ob/OlaHsd, Harlan Laboratories S.r.l.) (ob/ob) and control lean mice (
n
= 8) (CLM) were treated with melatonin (MEL)100 mg/kg per day for 8 weeks (from the5
th
to the 13
th
week of age).Data were compared from untreated ob/ob (
n
= 15) and CLM (
n
= 10) animals. Mesenteric small resistance arteries were dissected and mounted on a wire myograph. Concentration-response to norepinephrine was evaluated in vessels with intact PVAT (WF) and in vessels in which PVAT was removed (NoF) under normoxic and hypoxic (30’95% N
2
/5%CO
2
) conditions. Norepinephrine concentration-response curve was repeated with iberiotoxin(30’preincubation 100 nm/L).
Results
MEL significantly reduced the contractile response in NoF ob/ob and CLM vessels (ANOVA
P
= 0.014 and
P
= 0.049 respectively).The improvement after MEL was also seen in CLM NoF vessels during hypoxia(A-NOVA
p
< 0.05) and following preincubation with iberiotoxin(
P
< 0.05), with no significant improvements in ob/ob. Increases in contractility following hypoxia and iberiotoxin treatment were restored byMEL in Ob/Ob WF vessels (
P
= 0.013 and
P
= 0.036 respectively), whereas MEL only rescued the effects of hypoxia(
P
= 0.045) in CLM WF arteries. In conclusion, MEL exerts a protective effect in small vessels with and without PVAT from both ob/ob and CLM, counteracting the adverse effect of hypoxia and iberiotoxin in vessels with PVAT and in CLM vessels whitout PVAT. However, in Ob/Ob animals MEL rescues the effects only in the presence of PVAT indicating the importance of PVAT oxidative stress in vascular dysfunction observed in Ob/Ob animals.
It’s known that perivascular adipose tissue(PVAT)has an anticontractile effect maybe mediated by adiponectin, a physiological modulator of local vascular tone with mechanism still unknown. The PVAT ...function is lost in obese patients with the development of adipocyte hypertrophy, hypoxia, inflammation and oxidative stress(Circulation 2009; 119(12):1661–1670).The aim of the study was to investigate functional responses of small mesenteric arteries in a animal model of genetic obesity.
Materials and Methods
we investigated 8 obese mice(B6.V-Lep ob/OlaHsd, ob/ob) and8control lean mice (CLM).Mesenteric small resistance arteries(internal diameter about 200 µm) were dissected and mounted on a wire myograph. A concentration-response curve to norepinephrine(NE, from 10
−9
to 10
−5
Mol/l) was evaluated in vessels with intact prerivascular fat tissue(WF) and in vessels in which perivascular fat tissue was removed(NoF) in basal conditions and during vascular hypoxia (30’, 95%N
2
/5%CO
2
).Concentration response to NE was repeated in the presence of iberiotoxin(100 nm/L for 30’),a selective blocker of calcium-dependent potassium channels (BK
CA
),-that have been previously suggested to be involved in vascular tone regulation.
Results
are summarized in the figure(active media stress:KPa).The presence of PVAT reduced the contractile response to NE in both ob/ob(ANOVA p = 0.002 vs. noF)and CLM(ANOVA p= 0.001 vs. NoF),however, the effect was reduced in ob/ob compared with CLM. The anticontractile effect of PVAT completely disappeard with iberiotoxin preincubation(Maximum contraction to NE.ob/ ob:WF:176±47,68,NoF:218±66,02*,WF+iberiotoxin:289±98,06*;CLM:WF:118±53, 92, NoF:245±51.8*, WF+iberiotoxin:211±31*;*p<0.05 at least vs. WF) In conclusion, the anticontractile effect of perivascular fat is partially maintained in an animal model of genetic obesity. This effect may be related to the activity of BK
CA
channels, since it is blocked by iberiotoxin, a scorpion toxin that inhibits calcium-dependent potassium channels
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