NITRIC OXIDE (NO) BIOAVAILABILITY IN SUBCUTANEOUS SMALL RESISTANCE ARTERIES OF ESSENTIAL HYPERTENSIVE PATIENTS

The vascular effects of exogenous relaxin (Rln) treatment are well established and include decreased myogenic reactivity and enhanced relaxation responses to vasodilators in small resistance arteries. These vascular responses are reduced in older animals, suggesting that Rln is less effective in mediating arterial function with aging. The present study investigated the role of endogenous Rln in the aorta and the possibility that vascular dysfunction occurs more rapidly with aging in Rln-deficient ( Rln−/−) mice. We compared vascular function and underlying vasodilatory pathways in the aorta of male wild-type ( Rln+/+) and Rln−/− mice at 4 and 16 mo of age using wire myography. Superoxide production, but not nitrotyrosine or NADPH oxidase expression, was significantly increased in the aorta of young Rln−/− mice, whereas endothelial nitric oxide (NO) synthase and basal NO availability were both significantly decreased compared with Rln+/+ mice. In the presence of the cyclooxygenase inhibitor indomethacin, sensitivity to ACh was significantly decreased in young Rln−/− mice, demonstrating altered NO-mediated relaxation that was normalized in the presence of a membrane-permeable SOD or ROS scavenger. These vascular phenotypes were not exacerbated in old Rln−/− mice and, in most cases, did not differ significantly from old Rln+/+ mice. Despite the vascular phenotypes in Rln−/− mice, endothelium-dependent and -independent vasodilation were not adversely affected. Our data show a role for endogenous Rln in reducing superoxide production and maintaining NO availability in the aorta but also demonstrate that Rln deficiency does not compromise vascular function in this artery or exacerbate endothelial dysfunction associated with aging.

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TRPV4-mediated endothelial Ca2+ influx and vasodilation in response to shear stress

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00854.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. H466-H476 ◽

Cited By ~ 178

Author(s):

Suelhem A. Mendoza ◽

Juan Fang ◽

David D. Gutterman ◽

David A. Wilcox ◽

Aaron H. Bubolz ◽

...

Keyword(s):

Nitric Oxide ◽

Endothelial Cells ◽

Shear Stress ◽

Transient Receptor Potential ◽

Mesenteric Arteries ◽

Flow Mediated Dilation ◽

Potential Candidate ◽

Resistance Arteries ◽

Small Resistance ◽

Trpv4 Channel

The transient receptor potential vallinoid type 4 (TRPV4) channel has been implicated in the endothelial shear response and flow-mediated dilation, although the precise functions of this channel remain poorly understood. In the present study, we investigated the role of TRPV4 in shear stress-induced endothelial Ca2+ entry and the potential link between this signaling response and relaxation of small resistance arteries. Using immunohistochemical analysis and RT-PCR, we detected strong expression of TRPV4 protein and mRNA in the endothelium in situ and endothelial cells freshly isolated from mouse small mesenteric arteries. The selective TRPV4 agonist GSK1016790A increased endothelial Ca2+ and induced potent relaxation of small mesenteric arteries from wild-type (WT) but not TRPV4−/− mice. Luminal flow elicited endothelium-dependent relaxations that involved both nitric oxide and EDHFs. Both nitric oxide and EDHF components of flow-mediated relaxation were markedly reduced in TRPV4−/− mice compared with WT controls. Using a fura-2/Mn2+ quenching assay, shear was observed to produce rapid Ca2+ influx in endothelial cells, which was markedly inhibited by the TRPV4 channel blocker ruthenium red and TRPV4-specific short interfering RNA. Flow elicited a similar TRPV4-mediated Ca2+ entry in HEK-293 cells transfected with TRPV4 channels but not in nontransfected cells. Collectively, these data indicate that TRPV4 may be a potential candidate of mechanosensitive channels in endothelial cells through which the shear stimulus is transduced into Ca2+ signaling, leading to the release of endothelial relaxing factors and flow-mediated dilation of small resistance arteries.

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Effects of a Long-Term Treatment With Aliskiren or Ramipril on Structural Alterations of Subcutaneous Small-Resistance Arteries of Diabetic Hypertensive Patients

Hypertension ◽

10.1161/hypertensionaha.114.03380 ◽

2014 ◽

Vol 64 (4) ◽

pp. 717-724 ◽

Cited By ~ 16

Author(s):

Carolina De Ciuceis ◽

Carmine Savoia ◽

Emanuele Arrabito ◽

Enzo Porteri ◽

Monica Mazza ◽

...

Keyword(s):

Term Treatment ◽

Resistance Arteries ◽

Hypertensive Patients ◽

Structural Alterations ◽

Long Term Treatment ◽

Small Resistance

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Abstract 379: Circulating T Regulatory Lymphocytes and Microvascular Structural Alterations in Hypertensive Patients and Normotensive Subjects

Hypertension ◽

10.1161/hyp.62.suppl_1.a379 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Carolina De Ciuceis ◽

Claudia Rossini ◽

Paolo Airò ◽

Mirko Scarsi ◽

Angela Tincani ◽

...

Keyword(s):

Subcutaneous Fat ◽

Human Beings ◽

Resistance Arteries ◽

Hypertensive Patients ◽

Microvascular Remodeling ◽

Small Resistance ◽

Normotensive Subjects ◽

Positive Correlations ◽

Regulatory Lymphocytes ◽

T Lymphocytes Subpopulations

Background and Methods. Different components of the immune system, including innate immunity and adaptive immunity (T effector lymphocytes and T regulatory lymphocytes: Tregs) may be involved in the development of hypertension. In addition, it was recently demonstrated that Tregs may prevent angiotensin II-induced vascular injury/inflammation, while Th1, Th2 and Th17 may play a role in the progression of vascular remodeling. However, no data are available in human beings about relationships between T-lymphocyte subtypes and microvascular structure. In the present, preliminary study, we enrolled 7 normotensive subjects and 3 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. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph, morphological parameter were measured, in particular media to lumen ratio (M/L) was calculated. A peripheral blood sample was obtained before surgery for assessment of T lymphocytes subpopulations by flow cytometry. Results are summarized in the Table. RTE: recent thymus emigrant; naïve: no contact with antigens, TDEM: highly antigen-experienced cells that assume pro-apoptotic properties. Additional significant positive correlations were observed between M/L and Th17 effector lymphocytes: r=0.67, p<0.05). Conclusion Our data suggest that some lymphocytes subpopulations may be related to microvascular remodeling, and open the possibility to regress small artery remodeling in human by specific drug modulation of lymphocyte subtypes.

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Abstract P342: Sirt 1 on Endothelial Dysfunction in Small Arteries From Obese Patients

Hypertension ◽

10.1161/hyp.70.suppl_1.p342 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Agostino Virdis ◽

Stefano Masi ◽

Monica Nannipieri ◽

Daniela Guarino ◽

Marco Anselmino ◽

...

Keyword(s):

Endothelial Dysfunction ◽

Subcutaneous Tissue ◽

Normal Weight ◽

No Production ◽

Laparoscopic Bariatric Surgery ◽

Obese Patients ◽

Resistance Arteries ◽

Small Arteries ◽

Small Resistance ◽

No Bioavailability

Obesity is associated with endothelial dysfunction, characterised by a reduced nitric oxide (NO) bioavailability due to increased reactive oxygen species (ROS). Sirtuins, and more specifically Sirt-1, are enzymatic proteins involved in regulation of glucose metabolism, inflammation and intracellular levels of ROS. This study aimed to determine the role of Sirt-1 in regulating NO bioavailability of small resistance arteries isolated from subcutaneous tissue of obese patients. 10 subjects (5 with severe obesity, Ob; 5 normal weight controls, Ctrl) underwent biopsy of subcutaneous adipose tissue during laparoscopic bariatric surgery. Function of small arteries was assessed with pressure micromyography. Endothelial-dependent vasodilation (VDep) and NO production was assessed by acetylcholine (ACh, 0,001-100μM), with and without pre-incubation with L-NAME (100μM). The influence of sirtuins on NO bioavailability was assessed repeating Ach with a selective Sirt-1 agonist (SRT-1720, 1μM), alone or plus L-NAME. Ob showed a reduced response to Ach vs Ctrl (P<0.001), associated with a reduced inhibition of L-NAME on Ach (Ob: P=0.002; Ctrl: P<0.001). SRT-1720 improved the VDed induced by Ach (P<0.001) in Ob, although it did not reach values from Ctrl. The simultaneous incubation with L-NAME and SRT-1720 before Ach stimulation abolished the VDed obtained with the incubation of SRT-1720 in the Ob group (SRT-1720 vs SRT-1720+L-NAME: P<0.001). In small arteries of Ob, stimulation of Sirt-1 activity partially restores endothelial function due to an improved NO bioavailability.

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Abstract P256: Structural Alterations of Subcutaneous Small Resistance Arteries in Resistant Hypertension

Hypertension ◽

10.1161/hyp.66.suppl_1.p256 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Carolina De Ciuceis ◽

Claudia Rossini ◽

Maria Lorenza Muiesan ◽

Massimo Salvetti ◽

Enzo Porteri ◽

...

Keyword(s):

Blood Pressure ◽

Resistant Hypertension ◽

Subcutaneous Tissue ◽

Blood Pressure Monitoring ◽

Response To Treatment ◽

Large Artery ◽

Resistance Arteries ◽

Hypertensive Patients ◽

Structural Alterations ◽

Small Resistance

Background: It is was suggested that, in resistant hypertension, the presence of particularly pronounced microvascular alterations may contribute to explain the relative lack of response to treatment Patients and Methods: We investigated a population of 94 treated essential hypertensive patients. Secondary forms of hypertension were excluded, and in all patients a 24-hour blood pressure monitoring was performed in order to exclude a white coat effect. In all patients, we evaluated small resistance arteries morphology by a wire micromyographic approach. 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. We subdived our patents according to the presence or not of resistant hypertension (clinic blood pressure values above 140/90 mm Hg despite administration of three antihypertensive agent including a diuretic and 24-hour blood pressure values >130/80 mm Hg). Sixteen patients had true resistant hypertension, and were compared with the remaining 78 patients with non-resistant hypertension. Results: are summarized in the Table, The two groups were also different in terms of mean age (57±12 vs. 67±7 years, p=0.016 and pulse pressure/stroke volume, a rough index of large artery distensibility: 0.63±0.31 vs. 0.90±0.33, p=0.02). Conclusion: Hypertensive patients with true resistant hypertension have greater microvascular structural alterations compared with non-resistant hypertensive patients. This could partly explain the resistance to treatment and the high cardiovascular risk observed in these patients.

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Abstract P258: Essential Hypertension Induces Early Functional and Structural Vascular Aging in Small Resistance Arteries

Hypertension ◽

10.1161/hyp.66.suppl_1.p258 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Agostino Virdis ◽

Rosa Maria Bruno ◽

Emiliano Duranti ◽

Stefano Taddei

Keyword(s):

Repeated Measures ◽

Vascular Function ◽

Age Groups ◽

Progression Rate ◽

Resistance Arteries ◽

Hypertensive Patients ◽

Repeated Measures Anova ◽

Structural Alterations ◽

Small Resistance ◽

Subcutaneous Adipose

We evaluated cross-sectionally whether vascular remodeling is physiologically present in normal aging, and whether hypertension causes an acceleration of the aging process for vascular function and structure. 40 essential hypertensive patients (EH, age 44.9±13.2 years; BP, 157±8/99±3 mmHg) and 36 normotensive control individuals (Ctrl, age 44.7±12.7 years; BP: 128±7/80±4 mmHg) underwent laparoscopic surgery with subcutaneous adipose tissue biopsy. Small resistance arteries were studied by pressure micromiography. Endothelium-dependent and -independent vasodilation were evaluated by dose-response curve to Acetylcholine (ACh) and sodium nitroprusside (SNP). Maximum %inhibition by L-NAME on response to Ach was calculated. Structural alterations were assessed by media-lumen ratio (M/L). EH showed a reduced vasodilation to Ach (P<0.001), but not to SNP, compared to Ctrl. In both groups, %inhibition by L-NAME on response to ACh was inversely related to age (EH, r:-0.75; P<0.0001; Ctrl, r:-0.49; P<0.0001). NO availability was significantly reduced in EH as compared to Ctrl for each age group (<30 years: 22±6% vs 30±9%, P<0.05; 31-45 years: 17±3% vs 30±3%, P<0.0001; 46-60 years: 9±4% vs 21±6%, P60 years: 4±3% vs 13±3%, P<0.05). Age-hypertension interaction (Repeated measures ANOVA) was not significant (p= 0.25). EH showed an increased M/L (P<0.001) compared to Ctrl. In both groups, M/L was positively related to age. (EH, r:0.82; P<0.0001; Ctrl, r:0.50; P<0.0001). M/L was similar in EH and Ctrl for individuals <30 years, but greater in EH than Ctrl for the other age groups (31-45 years: 6.5±0.4% vs 5.6±0.4%, P<0.0001; 46-60 years: 7.4±0.5% vs 5.8±0.2%, P60 years: 7.9±0.3% vs 6.3±0.5%, P<0.0001). There was a significant age-hypertension interaction (Repeated measures ANOVA p= 0.0009). In small resistance arteries, aging is characterized by progressive reduction in NO availability and increased M/L. In hypertensive patients, NO availability is early reduced in comparison to Ctrl, but the progression rate with age appears to be similar. Conversely, structural alterations are influenced by hypertension only after 30 years of age, but the progression rate with age is steeper in the presence of hypertension.

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