scholarly journals The Reduced Uterine Perfusion Pressure (RUPP) Model of Preeclampsia Causes Decreased Capillary Perfusion in Skeletal Muscle

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Graham Fraser ◽  
Jude Morton ◽  
Sydney Schmidt ◽  
Stephane Bourque ◽  
Sandra Davidge ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Perfusion Pressure ◽  
Capillary Perfusion ◽  
Uterine Perfusion

scholarly journals Reduced uterine perfusion pressure decreases functional capillary density in skeletal muscle

2015 ◽  
Vol 309 (12) ◽  
pp. H2002-H2007 ◽  
Author(s):  
Graham M. Fraser ◽  
Jude S. Morton ◽  
Sydney M. Schmidt ◽  
Stephane Bourque ◽  
Sandra T. Davidge ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Continuous Flow ◽  
Perfusion Pressure ◽  
Capillary Density ◽  
Functional Capillary Density ◽  
Stopped Flow ◽  
Sprague Dawley ◽  
Capillary Perfusion ◽  
Pregnant State ◽  
Uterine Perfusion

The purpose of this study was to examine the functional and structural capillary density in the reduced uterine perfusion pressure (RUPP) model, which when performed during pregnancy is an established animal model of preeclampsia. We hypothesized that the RUPP model would be associated with capillary rarefaction and impaired capillary perfusion, which would be more pronounced in the pregnant state. Female Sprague-Dawley rats ( n = 32) were randomized to nonpregnancy (Nonpregnant) or breeding (Pregnant) at 12 wk of age and again to RUPP or SHAM surgeries on gestational day (GD) 14 (or equivalent age in nonpregnant rats). On GD 20 (or equivalent), capillary structure and perfusion of the extensor digitorum longus were imaged using digital intravital video microscopy. Functional videos were analyzed by a blinded observer to measure capillary density, expressed as capillaries per millimeter intersecting three staggered reference lines (200 μm). Flow was scored as the percentage of capillaries having 1) continuous, 2) intermittent, or 3) stopped flow. Total capillary density was not different between groups. There was a main effect of RUPP surgery resulting in decreased continuous flow vessels ( P < 0.01) and increased stopped flow ( P < 0.01), which was driven by differences between pregnant animals (Continuous flow: pregnant SHAM 80.1 ± 7.8% vs. pregnant RUPP 67.8 ± 11.2%, P < 0.05) (Stopped flow: pregnant SHAM 8.7 ± 3.2% vs. pregnant RUPP 17.9 ± 5.7%, P < 0.01). Our results demonstrate that the RUPP surgery is associated with a decrease in functional capillary density in skeletal muscle that is more pronounced in the pregnant state, which may contribute to the vascular pathophysiology observed in preeclampsia.

scholarly journals Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Claire Richards ◽  
Kimberly Sesperez ◽  
Michael Chhor ◽  
Sahar Ghorbanpour ◽  
Claire Rennie ◽  
...  
Keyword(s):  
Perfusion Pressure ◽  
Late Onset ◽  
Cardiac Fibroblasts ◽  
Immunofluorescent Staining ◽  
Collagen Deposition ◽  
Human Coronary Artery ◽  
Pregnant Rats ◽  
Cardiac Health ◽  
Increased Risk ◽  
Uterine Perfusion

Abstract Background Preeclampsia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preeclampsia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preeclampsia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preeclampsia. Methods The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta (n ≥ 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl, Icam1, Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE); n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling. Results The RUPP procedure induced significant increases in blood pressure (p < 0.001), collagen deposition (p < 0.001) and cardiac BNP45 (p < 0.05). It also induced a significant increase in cardiac FKBPL mRNA (p < 0.05) and protein  expression  (p < 0.01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression (p < 0.05). RUPP kidneys revealed an increase in average glomerular size (p < 0.05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE plasma (p < 0.05) and a trend towards increased FKBPL expression following treatment with EOPE plasma (p = 0.06). Conclusions The rat RUPP model induced cardiac, renal and placental features reflective of preeclampsia. FKBPL was increased in the hearts of RUPP rats and cardiac spheroids treated with plasma from women with preeclampsia, perhaps reflective of restricted angiogenesis and inflammation in this disorder. Elucidation of these novel FKBPL mechanisms in cardiac health in preeclampsia could be key in preventing future CVD.

Nonlinear Regulation of Capillary Perfusion in Relation to Ambient pO2 Changes in Skeletal Muscle

2005 ◽  
Vol 94 (3) ◽  
pp. 352-355 ◽  
Author(s):  
Masahiro Shibata ◽  
Shigeru Ichioka ◽  
Joji Ando ◽  
Tatsuo Togawa ◽  
Akira Kamiya
Keyword(s):  
Skeletal Muscle ◽  
Capillary Perfusion ◽  
Nonlinear Regulation

Reduced uterine perfusion pressure does not influence the endocannabinoid system (ECBS) transcripts in the rat model

Placenta ◽  
2013 ◽  
Vol 34 (9) ◽  
pp. A27
Author(s):  
Mauro Schenone ◽  
Zorica Janjetovic ◽  
Ramona Phinehas ◽  
Brian Brocato ◽  
Giancarlo Mari ◽  
...  
Keyword(s):  
Rat Model ◽  
Perfusion Pressure ◽  
Endocannabinoid System ◽  
Uterine Perfusion

Abstract 052: Placental Growth Factor (PlGF) Reduces Blood Pressure and Improves Endothelin Type B Receptor (ETBR)-Mediated Microvascular Dilation in Hypertensive Pregnant Rats

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Marc Q Mazzuca ◽  
Zongli Ren ◽  
Chen Lin ◽  
Jose S Possomato-Vieira ◽  
Minglin Zhu ◽  
...  
Keyword(s):  
Perfusion Pressure ◽  
Mesenteric Arteries ◽  
Hypertensive Disorder ◽  
Type B ◽  
Pregnant Rats ◽  
Western Blots ◽  
New Approach ◽  
Nitrite Production ◽  
Uterine Perfusion ◽  
Mesenteric Microvessels

Preeclampsia is a pregnancy-related hypertensive disorder (HTN-Preg) with an imbalance between anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and angiogenic PlGF, but the vascular targets involved are unclear. We have shown downregulation of endothelial ET B R in Preg rats with reduced uterine perfusion pressure (RUPP), and studies have shown increased plasma sFlt-1 in RUPP rats. We tested if raising PIGF/sFlt-1 ratio by infusing PIGF (10 μg/kg/day) in RUPP rats would improve BP and microvascular ET B R signaling, and vice versa, if lowering PIGF/sFlt-1 ratio by infusing sFlt-1 (10 μg/kg/day) in Preg rats increases BP and reduces ET B R signaling. On day 19, BP was recorded and mesenteric microvessels were isolated for measurement of diameter and [Ca 2+ ] i (fura-2 340/380 ratio). BP was in PlGF-RUPP 105±2 < RUPP 126±1 and in sFlt-Preg 125±4 > Norm-Preg 97±5 mmHg. ET-1 vasoconstriction was in PlGF-RUPP 62.6±3.0 < RUPP 83.4±5.3 and in sFlt-Preg 76.1±4.7 > Norm-Preg 52.1±3.2%. ET-1 caused parallel increases in microvascular [Ca 2+ ] i that was in PlGF-RUPP 0.87±0.02 < RUPP 0.92±0.01 and in sFlt-Preg 0.93±0.02 > Norm-Preg 0.85±0.01. Endothelium removal or microvessel treatment with ET B R antagonist BQ-788 enhanced ET-1 vasoconstriction and [Ca 2+ ] i in Norm-Preg and PlGF-RUPP, but not RUPP or sFlt-Preg. The ET B R agonists sarafotoxin 6c (S6c) and IRL-1620 caused relaxation that was in PlGF-RUPP 42.9±10.8, 38.0±11.2% > RUPP 4.7±3.4, 7.5±2.3% and in sFlt-Preg 3.1±1.0, 5.4±1.6% < Norm-Preg 29.9±7.8, 28.0±9.1%. L-NAME partially reduced ACh- and ET B R-induced relaxation in Norm-Preg, PlGF-RUPP, but not RUPP or sFlt-Preg, suggesting that PlGF improves the decreased NO-dependent and ET B R-mediated vasorelaxation in HTN-Preg. Basal, ACh-, S6c-, and IRL-1620-induced nitrate/nitrite production was enhanced in mesenteric arteries of PIGF-RUPP and Norm-Preg vs. RUPP rats. Western blots and immunohistochemistry revealed greater levels of endothelial ET B R in PlGF-RUPP and Norm-Preg vs. RUPP and sFlt-Preg. Thus improving PlGF/sFlt-1 balance reduces BP and ET-1 vasoconstriction, and enhances ET B R-mediated NO-dependent vasodilation in RUPP rats, and could be a new approach in the management of HTN-Preg.

scholarly journals Low Dose of IL-2 Normalizes Hypertension and Mitochondrial Function in the RUPP Rat Model of Placental Ischemia

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2797
Author(s):  
Evangeline Deer ◽  
Lorena M. Amaral ◽  
Nathan Campbell ◽  
Sarah Fitzgerald ◽  
Owen Herrock ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Rat Model ◽  
Low Dose ◽  
Perfusion Pressure ◽  
Chronic Inflammatory Response ◽  
Respiration Rates ◽  
Inflammatory Conditions ◽  
Uterine Perfusion ◽  
Placental Ischemia ◽  
New Onset

IL-2 is a cytokine released from CD4+T cells with dual actions and can either potentiate the inflammatory response or quell a chronic inflammatory response depending on its circulating concentration. IL-2 is elevated in many chronic inflammatory conditions and is increased during preeclampsia (PE). PE is characterized by new-onset hypertension during pregnancy and organ dysfunction and increasing evidence indicates that proinflammatory cytokines cause hypertension and mitochondrial (mt) dysfunction during pregnancy. The reduced uterine perfusion pressure (RUPP) model of placental ischemia is a rat model of PE that we commonly use in our laboratory and we have previously shown that low doses of recombinant IL-2 can decrease blood pressure in RUPP rats. The objective of this study was to determine the effects of a low dose of recombinant IL-2 on multi-organ mt dysfunction in the RUPP rat model of PE. We tested our hypothesis by infusing recombinant IL-2 (0.05 ng/mL) into RUPP rats on GD14 and examined mean arterial pressure (MAP), renal, placental and endothelial cell mt function compared to control RUPP. MAP was elevated in RUPP rats (n = 6) compared to controls (n = 5) (122 ± 5 vs. 102 ± 3 mmHg, p < 0.05), but was reduced by administration of LD recombinant IL-2 (107 ± 1 vs. 122 ± 5 mmHg, n = 9, p < 0.05). Renal, placental and endothelial mt ROS were significantly increased in RUPP rats compared to RUPP+ IL-2 and controls. Placental and renal respiration rates were reduced in RUPP rats compared to control rats but were normalized with IL-2 administration to RUPPs. These data indicate that low-dose IL-2 normalized multi-organ mt function and hypertension in response to placental ischemia.

scholarly journals Reduced Uterine Perfusion Pressure in Pregnant Rats Impairs Cerebral Vascular Myogenic Responses

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Michael J Ryan ◽  
Emily L Gilbert ◽  
Porter H Glover ◽  
Babbette D LaMarca ◽  
Joey P Granger
Keyword(s):  
Perfusion Pressure ◽  
Pregnant Rats ◽  
Myogenic Responses ◽  
Uterine Perfusion ◽  
Cerebral Vascular

Abstract P320: Proliferationof Endogenous T-regs Improves the Pathophysiology Associated with Placental Ischemia of Pregnancy

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Tarek Ibrahim ◽  
Lukasz Przybyl ◽  
Ashlyn C Harmon ◽  
Denise C Connelius ◽  
Mark W Cunningham ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Inflammatory Cytokines ◽  
Perfusion Pressure ◽  
Treg Cells ◽  
Proinflammatory Response ◽  
Regulatory Interactions ◽  
Uterine Perfusion ◽  
Placental Ischemia ◽  
Pro Inflammatory Cytokines ◽  
New Onset

Preeclampsia (PE), new onset hypertension during pregnancy, is associated with pro-inflammatory cytokines and decreased regulatory immune mechanisms such as Tregs, IL-10 and IL-4. We believe this decrease in immune regulatory mechanisms leads to an uncontrolled proinflammatory response which contributes to most of the pathophysiology associated with PE. The Reduced Uterine Perfusion Pressure, RUPP, rat model of induced placental ischemia exhibits similar characteristics as women with PE including high blood pressure, elevated pro-inflammatory cytokines and cells and decreased Tregs, IL-4 and IL-10. Therefore, we hypothesized that stimulating Tregs by administration of a superagonist (SA) would increase the Treg profile in the RUPP rats which could reduce pro-inflammatory cytokines and blood pressure. The RUPP procedure was performed at gestation day 14 (GD14); SA was administered intraperitoneally at GD15, GD18 carotid catheters inserted, and GD19 MAP and pup weight, serum and tissues were collected. MAP in NP rats was 98.6 mmHg ± 4.71, 122.2 mmHg ± 1.84 in RUPPs which was improved to 110.789mmHg ± 1.23 in RUPP+SA. Circulating FoxP3+ Treg cells were 5.987% ± 1.69% of total T-cells population in NP, 0.77% ± 0.49% in RUPP rats but increased to 11.218% ± 2.9% in RUPP+SA; Circulating IL-6 levels were 41.008 ± 4.79 pg/mL in NP, 108.26 ± 25.99 pg/mL in RUPP, and 40.37 ± 4.49 pg/mL in RUPP+SA, Administration of the SA to the NP rats did not affect IL-6 Levels in comparison to NP at 36.79 ± 3.9 pg/mL. Plasma IL-10 Levels were at 58.399 ± 9.527 pg/mL in NP rats, these levels were significantly decreased in the RUPP rats, 26.298 ± 4.33 pg/mL, and treatment of the RUPPs with the SA significantly increased plasma IL-10 levels to 51.5486 ± 3.329 pg/mL. When the SA was given to NP rats, the levels for IL-10 were significantly higher compared to any of the other groups at 85.5207 ± 9.067 pg/mL. Placental Pre-pro Endothelin-1 (PPET-1) was increased 44.42 ± 0.269 fold in RUPP compared to NP 1 ± 0.255, but was decreased to 18.78 ± 0.48 in RUPP+SA. These data suggest an important role for up-regulating Treg cells to enhance the immune regulatory interactions and lower the hypertension without causing further reduction in fetal weight in response to placental ischemia during pregnancy.

Release of nitric oxide and prostaglandin H2 to acetylcholine in skeletal muscle venules

1997 ◽  
Vol 272 (6) ◽  
pp. H2541-H2546 ◽  
Author(s):  
G. Dornyei ◽  
G. Kaley ◽  
A. Koller
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Perfusion Pressure ◽  
Thromboxane A2 ◽  
No Synthase ◽  
Gracilis Muscle ◽  
Vasoactive Agents ◽  
Before And After ◽  
Higher Doses

The role of endothelium in regulating venular resistance is not well characterized. Thus we aimed to elucidate the endothelium-derived factors involved in the mediation of responses of rat gracilis muscle venules to acetylcholine (ACh) and other vasoactive agents. Changes in diameter of perfusion pressure (7.5 mmHg)- and norepinephrine (10(-6) M)-constricted venules (approximately 225 microns in diam) to cumulative doses of ACh (10(-9) to 10(-4) M) and sodium nitroprusside (SNP, 10(-9) to 10(-4) M), before and after endothelium removal or application of various inhibitors, were measured. Lower doses of ACh elicited dilations (up to 42.1 +/- 4.7%), whereas higher doses of ACh resulted in smaller dilations or even constrictions. Endothelium removal abolished both ACh-induced dilation and constriction. In the presence of indomethacin (2.8 x 10(-5) M), a cyclooxygenase blocker, or SQ-29548 (10(-6) M), a thromboxane A2-prostaglandin H2 (PGH2) receptor antagonist, higher doses of ACh caused further dilation (up to 72.7 +/- 7%) instead of constriction. Similarly, lower doses of arachidonic acid (10(-9) to 10(-6) M) elicited dilations that were diminished at higher doses. These reduced responses were, however, reversed to substantial dilation by SQ-29548. The nitric oxide (NO) synthase blocker, N omega-nitro-L-arginine (L-NNA, 10(-4) M), significantly reduced the dilation to ACh (from 30.6 +/- 5.5 to 5.4 +/- 1.4% at 10(-6) M ACh). In contrast, L-NNA did not affect dilation to SNP. Thus ACh elicits the release of both NO and PGH2 from the venular endothelium.

Oxygen delivery to skeletal muscle fibers: effects of microvascular unit structure and control mechanisms

2003 ◽  
Vol 285 (3) ◽  
pp. H955-H963 ◽  
Author(s):  
Arthur Lo ◽  
Andrew J. Fuglevand ◽  
Timothy W. Secomb
Keyword(s):  
Skeletal Muscle ◽  
Muscle Activation ◽  
Tissue Oxygenation ◽  
Oxygen Sensing ◽  
Full Range ◽  
Muscle Fibers ◽  
Motor Units ◽  
Threshold Value ◽  
Control Mechanisms ◽  
Capillary Perfusion

The number of perfused capillaries in skeletal muscle varies with muscle activation. With increasing activation, muscle fibers are recruited as motor units consisting of widely dispersed fibers, whereas capillaries are recruited as groups called microvascular units (MVUs) that supply several adjacent fibers. In this study, a theoretical model was used to examine the consequences of this spatial mismatch between the functional units of muscle activation and capillary perfusion. Diffusive oxygen transport was simulated in cross sections of skeletal muscle, including several MVUs and fibers from several motor units. Four alternative hypothetical mechanisms controlling capillary perfusion were considered. First, all capillaries adjacent to active fibers are perfused. Second, all MVUs containing capillaries adjacent to active fibers are perfused. Third, each MVU is perfused whenever oxygen levels at its feed arteriole fall below a threshold value. Fourth, each MVU is perfused whenever the average oxygen level at its capillaries falls below a threshold value. For each mechanism, the dependence of the fraction of perfused capillaries on the level of muscle activation was predicted. Comparison of the results led to the following conclusions. Control of perfusion by MVUs increases the fraction of perfused capillaries relative to control by individual capillaries. Control by arteriolar oxygen sensing leads to poor control of tissue oxygenation at high levels of muscle activation. Control of MVU perfusion by capillary oxygen sensing permits adequate tissue oxygenation over the full range of activation without resulting in perfusion of all MVUs containing capillaries adjacent to active fibers.

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