scholarly journals Impaired dynamics of brain precapillary sphincters and first order capillaries explains reduced neurovascular functions in aging

2021 ◽  
Author(s):  
Changsi Cai ◽  
Stefan Andreas Zambach ◽  
Soeren Grubb ◽  
Kirsten Joan Thomsen ◽  
Barbara Lykke Lind ◽  
...  
Keyword(s):  
Blood Flow ◽  
Vascular Reactivity ◽  
Brain Aging ◽  
Capillary Density ◽  
Nitric Oxide Synthase Inhibitor ◽  
First Order ◽  
Age Related ◽  
Age Dependent ◽  
Synthase Inhibitor

The microvascular inflow tract (MIT), i.e. penetrating arterioles, precapillary sphincters and first order capillaries, is the bottleneck for brain blood flow and energy supply. However, the exact structural and functional alterations during aging remain elusive. Using in vivo 4-dimensional (xyzt) two-photon imaging, we showed an age-dependent decrease in vaso-responsivity, which was accompanied by reduced sensitivity of MIT to pinacidil and papaverine, and to vasoconstrictors endothelin-1 and to L-NAME, a nitric oxide synthase inhibitor. Reduced responsivity was accompanied by an age-dependent decrease in capillary density close to the arterioles and by loss of pericyte processes, whereas the number of pericyte somas and the pericyte αSMA density were preserved. The age-related reduction in vascular reactivity was most pronounced at precapillary sphincters, highlighting its crucial role for capillary blood flow regulation. Mathematical modeling further revealed dysregulated but protected pressure and flow in aged mice towards vasoconstriction. Prevention of reduced responsivity of the MIT may ameliorate the blood flow decrease associated with brain aging and age-related brain frailty.

Mechanisms of histamine-induced relaxation in bovine small adrenal cortical arteries

2005 ◽  
Vol 289 (6) ◽  
pp. E1058-E1063 ◽  
Author(s):  
David X. Zhang ◽  
Kathryn M. Gauthier ◽  
William B. Campbell
Keyword(s):  
Blood Flow ◽  
Mast Cell ◽  
Receptor Antagonist ◽  
Zona Glomerulosa ◽  
Receptor Antagonists ◽  
Vascular Events ◽  
Nitric Oxide Synthase Inhibitor ◽  
Aldosterone Production ◽  
Synthase Inhibitor

Adrenal steroidogenesis is closely correlated with increases in adrenal blood flow. Many reports have studied the regulation of adrenal blood flow in vivo and in perfused glands, but until recently few studies have been conducted on isolated adrenal arteries. The present study examined vasomotor responses of isolated bovine small adrenal cortical arteries to histamine, an endogenous vasoactive compound, and its mechanism of action. In U-46619-precontracted arteries, histamine (10−9-5 × 10−6 M) elicited concentration-dependent relaxations. The relaxations were blocked by the H1 receptor antagonists diphenhydramine (10 μM) or mepyramine (1 μM) (maximal relaxations of 18 ± 6 and 22 ± 6%, respectively, vs. 55 ± 5% of control) but only partially inhibited by the H2 receptor antagonist cimetidine (10 μM) and the H3 receptor antagonist thioperamide (1 μM). Histamine-induced relaxations were also blocked by the nitric oxide synthase inhibitor N-nitro-l-arginine (l-NA, 30 μM; maximal relaxation of 13 ± 7%) and eliminated by endothelial removal or l-NA combined with the cyclooxgenase inhibitor indomethacin (10 μM). In the presence of adrenal zona glomerulosa (ZG) cells, histamine did not induce further relaxations compared with histamine alone. Histamine (10−7-10−5 M) concentration-dependently increased aldosterone production by adrenal ZG cells. Compound 48/80 (10 μg/ml), a mast cell degranulator, induced significant relaxations (93 ± 0.6%), which were blocked by l-NA plus indomethacin or endothelium removal, partially inhibited by the combination of the H1, H2, and H3 receptor antagonists, but not affected by the mast cell stabilizer sodium cromoglycate (1 mM). These results demonstrate that histamine causes direct relaxation of small adrenal cortical arteries, which is largely mediated by endothelial NO and prostaglandins via H1 receptors. The potential role of histamine in linking adrenal vascular events and steroid secretion requires further investigation.

Abstract 18060: TRAIL Promotes Angiogenesis and Ischemia-Induced Neovascularisation via NOX4, H2O2 and Nitric Oxide-Dependent Mechanisms

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Belinda A Di Bartolo ◽  
Sian P Cartland ◽  
Leonel Prado-Lourenco ◽  
Nor Saadah M Azahri ◽  
Thuan Thai ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Angiogenic Factor ◽  
Tubule Formation ◽  
Nitric Oxide Synthase Inhibitor ◽  
Therapeutic Implications ◽  
Synthase Inhibitor ◽  
Oxide Synthase ◽  
First Time

Background: Angiogenesis and neovascularization are essential processes that follow ischemia insults. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) not only induces endothelial cell (EC) death and inhibits angiogenesis, but also promotes EC migration, invasion and proliferation in vitro . These seemingly opposite effects make its role in angiogenesis in vivo unclear. Using TRAIL -/- and wild-type mice, we sought to determine the role of TRAIL in angiogenesis and neovascularisation. We also sought mechanisms in vitro . Methods and Results: Reduced vascularisation assessed by real-time in vivo 3D Vevo ultrasound imaging and CD31 staining was observed in TRAIL -/- mice 28 d after hindlimb ischemia. Moreover, reduced capillary formation and increased apoptosis was evident in TRAIL -/- muscles even at 3 d after ischemic surgery. We have previously shown that fibroblast growth factor-2 (FGF-2), a potent angiogenic factor, regulates TRAIL gene expression in vascular smooth muscle cells. Indeed, FGF-2 also regulates TRAIL expression in ECs, and FGF-2-inducible proliferation, migration and tubule formation was inhibited with siRNA targeting TRAIL. Notably, both FGF-2 and TRAIL significantly increased NOX4 expression. TRAIL-inducible angiogenic activity in ECs was inhibited with siRNAs targeting NOX4, and consistent with these, NOX4 mRNA was reduced in 3 d ischemic hindlimbs of TRAIL -/- mice. TRAIL stimulated intracellular H 2 O 2 levels in ECs, and TRAIL-inducible proliferation, migration and tubule formation was inhibited with not only PEG-catalase, a H 2 O 2 scavenger, but also blocked with L-NAME, a nitric oxide synthase inhibitor. Conclusions: This is the first demonstration showing that TRAIL promotes angiogenesis in vivo . We show for the first time that the TRAIL stimulates NOX4 expression to mediate nitric oxide-dependent angiogenic effects. This has significant therapeutic implications such that TRAIL may improve the angiogenic response to ischemia and increase perfusion recovery in patients with CVD and diabetes.

Abstract 1421: In Vivo Measurement of Flow-Mediated Vasodilation in Living Rats using High Resolution Ultrasound: Age-Dependent Endothelial Dysfunction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Christian Heiss ◽  
Richard E Sievers ◽  
Nicolas Amabile ◽  
Tony Y Momma ◽  
Shobha Natarajan ◽  
...  
Keyword(s):  
High Resolution ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Femoral Artery ◽  
Reactive Hyperemia ◽  
Surrogate Marker ◽  
Flow Measurements ◽  
Age Related ◽  
Age Dependent

In humans, endothelial function serves as a surrogate marker for cardiovascular health and is measured as changes in arterial diameter after temporary ischemia (flow-mediated dilation; FMD). We developed an FMD-related approach to study conduit artery vasodilation in living rats, and demonstrate a reduction in FMD in older versus younger animals consistent with age-related endothelial dysfunction. Diameter and Doppler-flow measurements were obtained from the femoral artery using high-resolution ultrasound (35 MHz). We observed dose-dependent vasodilation using both endothelium-dependent and endothelium-independent pharmacologic vasodilators (acetylcholine and nitroglycerine). Flow-dependent vasodilation was observed in response to flow increase induced both by adenosine and local saline infusion. Transient hindlimb ischemia led to reactive hyperemia with sequential flow velocity increase and femoral artery dilation, the latter of which was completely abolished by NO-synthase (NOS) inhibition with L-NMMA. To demonstrate its applicability in a model of endothelial dysfunction, we show that FMD is significantly reduced in older versus younger animals. While FMD was completely NOS-dependent in younger animals, NOS-dependent mechanisms accounted for only half of the FMD in older animals, with the remainder being blocked by charybdotoxin (CTx) and apamin suggesting contribution of endothelium-derived-hyperpolarizing-factor. Using this new integrative physiologic model to reproducibly study FMD in living rats, we show that age-dependent endothelial dysfunction is accompanied by a shift in mechanisms underlying vasodilatory endothelial function.

scholarly journals Imaging of the Intestinal Microcirculation during Acute and Chronic Inflammation

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 418
Author(s):  
Kayle Dickson ◽  
Hajer Malitan ◽  
Christian Lehmann
Keyword(s):  
Blood Flow ◽  
Multiorgan Failure ◽  
Capillary Density ◽  
Intestinal Microcirculation ◽  
Inflammatory Conditions ◽  
Microcirculatory Disturbances ◽  
Vessel Integrity ◽  
Irritable Bowel ◽  
Acute And Chronic Inflammation

Because of its unique microvascular anatomy, the intestine is particularly vulnerable to microcirculatory disturbances. During inflammation, pathological changes in blood flow, vessel integrity and capillary density result in impaired tissue oxygenation. In severe cases, these changes can progress to multiorgan failure and possibly death. Microcirculation may be evaluated in superficial tissues in patients using video microscopy devices, but these techniques do not allow the assessment of intestinal microcirculation. The gold standard for the experimental evaluation of intestinal microcirculation is intravital microscopy, a technique that allows for the in vivo examination of many pathophysiological processes including leukocyte-endothelial interactions and capillary blood flow. This review provides an overview of changes in the intestinal microcirculation in various acute and chronic inflammatory conditions. Acute conditions discussed include local infections, severe acute pancreatitis, necrotizing enterocolitis and sepsis. Inflammatory bowel disease and irritable bowel syndrome are included as examples of chronic conditions of the intestine.

Endothelin-1 and pancreatic islet vasculature: studies in vivo and on isolated, vascularly perfused pancreatic islets

2007 ◽  
Vol 292 (6) ◽  
pp. E1616-E1623 ◽  
Author(s):  
En Yin Lai ◽  
A. Erik G. Persson ◽  
Birgitta Bodin ◽  
Örjan Källskog ◽  
Arne Andersson ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pancreatic Islet ◽  
Vascular Reactivity ◽  
Blood Perfusion ◽  
Receptor Subtype ◽  
Endothelin 1 ◽  
Islet Blood Flow ◽  
Endothelin B

Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor, which also stimulates insulin release. The aim of the present study was to evaluate whether exogenously administered ET-1 affected pancreatic islet blood flow in vivo in rats and the islet arteriolar reactivity in vitro in mice. Furthermore, we aimed to determine the ET-receptor subtype that was involved in such responses. When applying a microsphere technique for measurements of islet blood perfusion in vivo, we found that ET-1 (5 nmol/kg) consistently and markedly decreased total pancreatic and especially islet blood flow, despite having only minor effects on blood pressure. Neither endothelin A (ETA) receptor (BQ-123) nor endothelin-B (ETB) receptor (BQ-788) antagonists, alone or in combination, could prevent this reduction in blood flow. To avoid confounding interactions in vivo, we also examined the arteriolar vascular reactivity in isolated, perfused mouse islets. In the latter preparation, we demonstrated a dose-dependent constriction in response to ET-1. Administration of BQ-123 prevented this, whereas BQ-788 induced a right shift in the response. In conclusion, the pancreatic islet vasculature is highly sensitive to exogenous ET-1, which mediates its effect mainly through ETA receptors.

Generalized Dilation of the Visceral Microvasculature by Peritoneal Dialysis Solutions

2002 ◽  
Vol 22 (5) ◽  
pp. 593-601 ◽  
Author(s):  
El Rasheid Zakaria ◽  
David A. Spain ◽  
Patrick D. Harris ◽  
R. Neal Garrison
Keyword(s):  
Blood Flow ◽  
Peritoneal Dialysis ◽  
Terminal Ileum ◽  
Vascular Reactivity ◽  
Nitric Oxide Donor ◽  
Buffer System ◽  
Dialysis Solution ◽  
Dialysis Solutions ◽  
Peritoneal Dialysis Solutions

Objectives Conventional peritoneal dialysis solutions are vasoactive. This vasoactivity is attributed to hyperosmolality and lactate buffer system. This study was conducted to determine if the vasodilator property of commercial peritoneal dialysis solutions is a global phenomenon across microvascular levels, or if this vasodilation property is localized to certain vessel types in the small intestine. Design Experimental study in a standard laboratory facility. Interventions Hemodynamics of anesthetized rats were monitored while the terminal ileum was prepared for in vivo intravital microscopy. Vascular reactivity of inflow arterioles (A1), branching (A2), and arcade, as well as pre-mucosal (A3) arterioles was assessed after suffusion of the terminal ileum with a non-vasoactive solution or a commercial 4.25% glucose-based solution (Delflex; Fresenius USA, Ogden, Utah, USA). Vascular reactivity of three different level venules was also assessed. Maximum dilation response was obtained from sequential applications of the endothelial-dependent dilator, acetylcholine (10–5 mol/L), and the endothelial-independent nitric oxide donor, sodium nitroprusside (NTP; 10–4mol/L). Results Delflex induced an instant and sustained vasodilation that averaged 28.2% ± 2.4% of baseline diameter in five different-level arterioles, ranging in size between 7 μ and 100 μ. No significant vascular reactivity was observed in three different-level venules. Delflex increased intestinal A1 blood flow from baseline 568 ± 31 nL/second to 1049 ± 46 nL/sec ( F = 24.7, p < 0.001). Similarly, intestinal venous outflow increased to 435 ± 17 nL/sec from a baseline outflow of 253 ± 59 nL/sec ( F = 4.7, p < 0.05). Adjustment of the initial pH of Delflex from 5.5 to 7.4 resulted in similar microvascular responses before pH adjustment. Conclusions Ex vivo exposure of intestinal arterioles to conventional peritoneal dialysis solutions produces a sustained and generalized vasodilation. This vasoactivity is independent of arteriolar level and the pH of the solution. Dialysis solution-mediated vasodilation is associated with doubling of A1 intestinal arteriolar blood flow. Addition of NTP at an apparent clinical dose does not appear to produce any further significant arteriolar dilation than that induced by dialysis solution alone. Experimental data that estimate the exchange vessel surface area per unit volume of tissue will be required to make a correlation with permeability in order to extrapolate our findings to clinical in vivo conditions.

scholarly journals Reduction of Functional Capillary Density in Human Brain after Stroke

1990 ◽  
Vol 10 (3) ◽  
pp. 317-326 ◽  
Author(s):  
Albert Gjedde ◽  
Hiroto Kuwabara ◽  
Antoine M. Hakim
Keyword(s):  
Blood Flow ◽  
Brain Tissue ◽  
Capillary Density ◽  
Functional Capillary Density ◽  
Functional Density ◽  
Hemodynamic Variables ◽  
Cortical Gray Matter ◽  
Cerebral Ischemic ◽  
Reduced Density

The blood flow of brain tissue often returns to normal after an ischemic episode. As “luxury” rather than “reactive” reperfusion, this hyperemia is associated with low metabolism. It is not known to what extent the high blood flow accompanies a high, normal, or low density of capillaries. The resolution of this question may indicate whether the functional capillary density is variable and, if so, whether it is coupled to blood flow or metabolism. To answer these questions, we defined functional capillaries as capillaries that transport glucose. We then calculated the density of functional capillaries ( Dcap) and the mean time of transit of blood through the capillaries ( tcap) from hemodynamic variables obtained in vivo by positron tomography of five patients afflicted by cerebral ischemic stroke. Each patient was studied twice, within 36 h of the insult and 1 week later. We identified nominally “ischemic” regions in the first study as cortical gray matter regions, contiguous with the ischemic focus, in which the magnitude of blood flow did not exceed 20 ml 100 g−1 min−1. In these regions, values of metabolism and functional capillary density were proportionately low compared with normal values obtained in the contralateral hemisphere. The studies revealed a reduction of the functional density of exchange vessels in postischemic brain tissue as soon as 36 h after the insult. In “ischemic” regions, within 36 h of the insult, the net extraction of oxygen was inversely related to the capillary transit time and appeared to be limited mainly by the low functional density of the capillaries. Contrary to expectations, the reduced density persisted, even when more than adequate perfusion of the tissue returned. For these reasons, we concluded that changes of the capillary density were associated with changes of the metabolism of the tissue rather than with blood flow.

Stereoselective Differences in the Vasorelaxing Effects of S(+) and R(-) Ketamine on Rat Isolated Aorta 

1998 ◽  
Vol 88 (3) ◽  
pp. 718-724 ◽  
Author(s):  
Adriani Kanellopoulos ◽  
Gunther Lenz ◽  
Bernd Muhlbauer
Keyword(s):  
Nitric Oxide ◽  
Adenosine Triphosphate ◽  
Blocking Agent ◽  
Rat Aorta ◽  
K Channel ◽  
Nitric Oxide Synthase Inhibitor ◽  
Nitric Oxide Release ◽  
Racemic Ketamine ◽  
Synthase Inhibitor

Background S(+) ketamine, because of its higher anesthetic potency and lower risk of psychotomimetic reactions, has been suggested to be superior to presently available racemic ketamine. The racemate is a direct vasodilator in vivo, and thus the authors investigated the vasorelaxing effects of ketamine enantiomers on rat aorta. Methods Rat isolated aortic rings with and without endothelium were contracted with 3 x 10(-7) M norepinephrine. Then 10(-5) to 3 x 10(-3) M S(+), R(-), or racemic ketamine were added cumulatively. Vascular responses to ketamine were further studied in rings pretreated with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (NNLA), the adenosine triphosphate-sensitive K+ channel antagonist glibenclamide, and the L-type calcium channel blocking agent D888. Results Ketamine enantiomers and the racemate produced concentration-dependent vasorelaxation. The relaxing effect of S(+) ketamine was significantly weaker compared with R(-) ketamine and the racemate reflected by the half-maximum effective concentration (EC50) values of 11.6 x 10(-4), 4.8 x 10(-4), and 6 x 10(-4) M, respectively. Removal of the endothelium and NNLA or glibenclamide pretreatment did not significantly alter the vasorelaxing effect of ketamine. In contrast, D888 pretreatment significantly shifted the concentration-effect curves of both S(+) and R(-) ketamine rightward (EC50 values of 18.9 x 10(-4) and 8.5 x 10(-4) M, respectively), whereas the difference between the isomers was not affected. Conclusions Vasorelaxation by ketamine enantiomers is quantitatively stereoselective: The effect of S(+)ketamine is significantly weaker compared with that of the racemate and R(-) ketamine. This stereoselective difference is not due to nitric oxide release, activation of adenosine triphosphate-sensitive potassium channels, or differential inhibition of L-type calcium channels.

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