scholarly journals OR17-06 Transglutaminase 2 Inhibition Reduces Aortic Stiffness in Western Diet-Fed Female Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Bhavana Chinnakotla ◽  
Camila Margarita Manrique Acevedo ◽  
Padilla Jaume ◽  
Makenzie L Woodford ◽  
Annayya R Aroor ◽  
...  
Keyword(s):  
Aortic Stiffness ◽  
Weight Control ◽  
Ex Vivo ◽  
Transglutaminase 2 ◽  
Competitive Inhibitor ◽  
Tolerance Test ◽  
Western Diet ◽  
Arterial Stiffening ◽  
Female Mice

Abstract Widespread consumption of diets high in fat, sugars and salt (Western diet, WD) is associated arterial stiffening, which is a major independent risk factor for cardiovascular disease (CVD). Notably, while WD feeding increases the risk of CVD in both males and females, the latter are more prone to develop arterial stiffening. However, the mechanisms underlying WD-induced arterial stiffening are poorly understood, particularly in females, and there are currently no specific treatments targeted at vascular stiffening.Tissue transglutaminase 2 (TG2) is an enzyme that mediates the cross-linking and stabilization of extracellular matrix proteins such as collagen, and promotes the polymerization of actin stress fibers of the cytoskeleton. It is ubiquitously expressed and abundantly present in the vasculature. Mounting evidence implicates TG2 activation in the pathogenesis of arterial stiffening and vascular fibrosis. Herein we propose that TG2 activation is central to WD-induced arterial stiffening and sought to determine the efficacy of cystamine (a non-specific competitive inhibitor of TG2) for reducing arterial stiffening in the setting of WD consumption. Accordingly, we fed 20 female mice (4 weeks old) a WD (4.65 kcal/g of food, fat 46% kcals, high-fructose corn syrup 17.5%, sucrose 17.5%, protein 17.6%, salt 1.6%) for 43 weeks. Ten of these mice received cystamine (40 mg/Kg/d in the drinking water) during their last 8 weeks on the WD. Another group of female mice (n=10) fed regular chow was used as reference controls. Aortic stiffness was measured in vivo via ultrasound-based pulse wave velocity and ex vivo by aortic explant atomic force microscopy. Vasomotor responses were assessed in isolated aortic rings via wire myography.Cystamine did not influence glucose homeostasis (intraperitoneal glucose tolerance test) or blood pressure (tail-cuff) (control 77.208±2.229 mm Hg versus WD 77.208±6.077 versus WD+Cystamine 76.297±7.894), but it was associated with increased body weight (control 26.860±2.215 grams versus WD 25.320±2.889 versus WD+Cystamine 33.220±4.848, p<0.05). Notably, cystamine reduced aortic stiffness in WD-fed mice both in vivo and ex vivo such that differences between chow-fed and WD-fed mice were normalized (control 5.294±1.713 versus WD 11.735±5.962 p≤0.05, control 5.294±1.713 versus WD+Cystamine 3.940±0.378 KPa, p<0.05). In addition, WD-induced impairments in endothelium-independent vasorelaxation (i.e. responses to sodium nitroprusside) were restored with cystamine. Collectively, our data show that cystamine reduces aortic stiffness and improves endothelium-independent vasorelaxation in female mice chronically exposed to WD, and that these effects occur despite an increase in weight gain. These findings implicate TG2 as a promising therapeutic target for reducing arterial stiffening in the context of chronic over-nutrition in females.

scholarly journals Regional variation in arterial stiffening and dysfunction in Western diet-induced obesity

2015 ◽  
Vol 309 (4) ◽  
pp. H574-H582 ◽  
Author(s):  
Shawn B. Bender ◽  
Jorge A. Castorena-Gonzalez ◽  
Mona Garro ◽  
Constantino C. Reyes-Aldasoro ◽  
James R. Sowers ◽  
...  
Keyword(s):  
Coronary Arteries ◽  
Regional Variation ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Transforming Growth Factor Β ◽  
Western Diet ◽  
Internal Elastic Lamina ◽  
Arterial Stiffening ◽  
Femoral Arteries

Increased central vascular stiffening, assessed in vivo by determination of pulse wave velocity (PWV), is an independent predictor of cardiovascular event risk. Recent evidence demonstrates that accelerated aortic stiffening occurs in obesity; however, little is known regarding stiffening of other disease-relevant arteries or whether regional variation in arterial stiffening occurs in this setting. We addressed this gap in knowledge by assessing femoral PWV in vivo in conjunction with ex vivo analyses of femoral and coronary structure and function in a mouse model of Western diet (WD; high-fat/high-sugar)-induced obesity and insulin resistance. WD feeding resulted in increased femoral PWV in vivo. Ex vivo analysis of femoral arteries revealed a leftward shift in the strain-stress relationship, increased modulus of elasticity, and decreased compliance indicative of increased stiffness following WD feeding. Confocal and multiphoton fluorescence microscopy revealed increased femoral stiffness involving decreased elastin/collagen ratio in conjunction with increased femoral transforming growth factor-β (TGF-β) content in WD-fed mice. Further analysis of the femoral internal elastic lamina (IEL) revealed a significant reduction in the number and size of fenestrae with WD feeding. Coronary artery stiffness and structure was unchanged by WD feeding. Functionally, femoral, but not coronary, arteries exhibited endothelial dysfunction, whereas coronary arteries exhibited increased vasoconstrictor responsiveness not present in femoral arteries. Taken together, our data highlight important regional variations in the development of arterial stiffness and dysfunction associated with WD feeding. Furthermore, our results suggest TGF-β signaling and IEL fenestrae remodeling as potential contributors to femoral artery stiffening in obesity.

Abstract 012: Mineralocorticoid Receptors Mediate Western Diet-Induced Macrophage Polarization and Aortic Stiffness

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Guanghong Jia ◽  
Annayya R Aroor ◽  
Vincent G DeMarco ◽  
Zhe Sun ◽  
Brian P Bostick ◽  
...  
Keyword(s):  
Aortic Stiffness ◽  
Low Dose ◽  
Ex Vivo ◽  
Macrophage Polarization ◽  
Western Diet ◽  
Marker Genes ◽  
Mineralocorticoid Receptors ◽  
Expression Ratio

Mineralocorticoid receptors (MRs) are expressed in vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells (ECs) and signaling through these receptors may play a key role in development of aortic stiffness. Accordingly, we hypothesized that these vascular MRs are involved in the western diet (WD) - induced macrophage polarization and aortic stiffness. The stiffness of primary cultured VSMC and tissue ECs or VSMCs from mice was measured using cell nano-indentation with atomic force microscopy (AFM). Both Ang II (100 nM) and aldosterone (10 nM) increased VSMC stiffness in vitro. Also, B57 mice fed a WD for 16 weeks increased EC and VSMC stiffness as determined by in vivo pulse wave velocity and ex vivo AFM techniques. The elevated aortic stiffness was accompanied by increased mRNA expression of M1 markers MCP-1, CD 86, and CD11b. However, treatment with low dose spironolactone (Sp) (1.0 mg/kg/day), a dose not affecting blood pressure, significantly attenuated WD-induced increases in stiffness in murine ECs and VSMCs. Sp increased M2 marker IL10 and the expression ratio of M2/M1 marker genes in aorta by real time PCR. Interestingly, mice with EC MR knockout did not develop WD- induced aortic vasodilation dysfunction under both Ach and SNP (10-9-10-4 mol/L) stimulation. Furthermore, low dose Sp inhibited WD- caused up-regulation of ERK 1/2 and down-regulation Akt/eNOS signaling pathways in the aorta. These findings support the notion that increased vascular and macrophage MR signaling play a key role in macrophage polarization and associated aortic stiffness that result from consuming a WD high in fructose and fat.

Abstract 616: MicroRNA miR-29b is a Mediator of Aortic Stiffness and Hypertension in a Murine Model of Type 2 Diabetes Mellitus

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Uwe Raaz ◽  
Isabel N Schellinger ◽  
Lars Maegdefessel ◽  
Joshua M Spin ◽  
Gerd Hasenfuss ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Pulse Pressure ◽  
Aortic Stiffness ◽  
Target Genes ◽  
Ex Vivo ◽  
Matrix Remodeling ◽  
Collagen Deposition ◽  
Arterial Stiffening ◽  
Vascular Stiffening ◽  
Aortic Stiffening

Background: Accelerated arterial stiffening is a complication of diabetes mellitus and associated with the development of hypertension. Arterial stiffening results from extensive extracellular matrix remodeling (elastin breakdown, collagen accumulation). MicroRNA miR-29b directly regulates the expression of genes governing fibrosis (such as COL1A1, COL3A1) and elastin breakdown ( MMP2, MMP9 ). However, its impact on aortic stiffness is unclear. Objective: This study was designed to investigate the role of miR-29b as potential mediator of diabetic aortic stiffening. Methods and Results: Serial ex vivo mechanical testing of the thoracic aorta and volume-pressure recording (VPR) based tail-cuff blood pressure measurements revealed that aortic stiffening precedes blood (pulse) pressure elevations in diabetic db/db mice. Vascular stiffening was accompanied by increased elastin fragmentation and collagen deposition (EvG and Picrosirius Red staining). qRT-PCR, in-situ hybridization and immunohistochemistry revealed decreased expression of miR-29b and de-repression of target genes ( Col1A1, COL3A1, MMP2, MMP9 ) in db/db mice compared to controls. Investigating the mechanistic significance of miR-29b for arterial stiffening, forced downregulation of miR-29b (via systemic LNA-miR-29b inhibitor application) results in enhanced elastin fragmentation, increased medial collagen deposition, aortic stiffness and augmented pulse pressure. Conclusions: In conclusion this study identifies miR-29b as a regulator and potential therapeutic target of diabetic aortic stiffening.

scholarly journals Gonadotrope Plasticity at Cellular and Population Levels

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 4729-4739 ◽  
Author(s):  
Zahara Alim ◽  
Cheryl Hartshorn ◽  
Oliver Mai ◽  
Iain Stitt ◽  
Colin Clay ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Anterior Pituitary ◽  
Ex Vivo ◽  
Single Cells ◽  
Anterior Pituitary Gland ◽  
Female Mice ◽  
Model Animal ◽  
Pituitary Glands ◽  
Acute Changes

Abstract Hormone-secreting cells within the anterior pituitary gland may form organized and interdigitated networks that adapt to changing endocrine conditions in different physiological contexts. For gonadotropes, this might reflect a strategy to cope with acute changes throughout different female reproductive stages. The current study examined gonadotropes in female mice at characteristically different hormonal stages: prepubertal, postpubertal, and lactating. Gonadotrope plasticity was examined at the level of the whole population and single cells at different stages by imaging both fixed and live pituitary slices. The use of a model animal providing for the identification of selectively fluorescent gonadotropes allowed the particular advantage of defining cellular plasticity specifically for gonadotropes. In vivo analyses of gonadotropes relative to vasculature showed significantly different gonadotrope distributions across physiological states. Video microscopy studies using live slices ex vivo demonstrated pituitary cell plasticity in the form of movements and protrusions in response to GnRH. As positive feedback from rising estradiol levels is important for priming the anterior pituitary gland for the LH surge, experiments provide evidence of estradiol effects on GnRH signaling in gonadotropes. The experiments presented herein provide new insight into potential plasticity of gonadotropes within the anterior pituitary glands of female mice.

In vivo brain phosphocreatine and ATP regulation in mice fed a creatine analog

1997 ◽  
Vol 272 (5) ◽  
pp. C1567-C1577 ◽  
Author(s):  
D. Holtzman ◽  
R. Meyers ◽  
E. O'Gorman ◽  
I. Khait ◽  
T. Wallimann ◽  
...  
Keyword(s):  
Reaction Rate ◽  
Ex Vivo ◽  
Competitive Inhibitor ◽  
High Energy ◽  
Energy Deficit ◽  
Resonance Spectroscopy ◽  
Atp Metabolism ◽  
Creatine Transport ◽  
Atp Regulation

Mitochondrial and cytosolic creatine kinase (CK) isozymes are active in cells with high and variable ATP metabolic rates. beta-Guanidinopropionic acid (GPA), a competitive inhibitor of creatine transport, was used to study the hypothesis that the creatine-CK-phosphocreatine (PCr) system is important in regulating brain ATP metabolism. The CK-catalyzed reaction rate and reactant concentrations were measured in vivo with 31P nuclear magnetic resonance spectroscopy during energy deficit (hypoxia) or high-energy turnover (seizures) states in urethane-anesthetized mice fed GPA, creatine, or standard chow (controls). Brain phosphagen (i.e., cellular energy reserves) or PCr plus phosphorylated GPA (GPAP) concentrations were equal. The phosphagen-to-NTP ratio was lower than in controls. In vivo CK reaction rate decreased fourfold, whereas ex vivo CK activity that was biochemically measured was doubled. During seizures, CK-catalyzed fluxes increased only in GPA-fed mice. Phosphagen increased in GPA-fed mice, whereas PCr decreased in controls. Survival was higher and brain phosphagen and ATP losses were less for hypoxic GPA-fed mice than for controls. In contrast to mice fed GPA, hypoxic survival and CK reactant concentrations during hypoxia and seizures were the same in creatine-fed mice and controls. Thus GPA, GPAP, or adaptive changes in ATP metabolism stabilize brain ATP and enhance survival during hypoxia in mice.

Aortic stiffness in vivo in hypertensive rat via echo-tracking: analysis of the pulsatile distension waveform

2011 ◽  
Vol 301 (2) ◽  
pp. H382-H390 ◽  
Author(s):  
Christine Vayssettes-Courchay ◽  
Christophe Ragonnet ◽  
Marc Isabelle ◽  
Tony J. Verbeuren
Keyword(s):  
Nitric Oxide ◽  
Aortic Stiffness ◽  
Vascular Wall ◽  
Stiffness Index ◽  
Large Artery ◽  
Arterial Stiffening ◽  
Wall Properties ◽  
Wistar Kyoto ◽  
Echo Tracking

Large-artery stiffening is a major risk factor in aging and hypertension. Elevated blood pressure (BP) and vascular wall properties participate in arterial stiffening; we aimed to evaluate their respective role by combining echo-tracking and the spontaneously hypertensive rats (SHR) treated with low doses of a nitric oxide synthase inhibitor, shown to have arterial stiffening. Normotensive [Wistar-Kyoto (WKY)], SHR, and SHR treated for 2 wk with NG-nitro-l-arginine methyl ester (SHRLN) were anesthetized; BP and distension (pulsatile displacement) of the aortic walls with the ArtLab echo-tracking device were measured. Stiffness index increased in SHRLN vs. SHR; compliance, distensibility, and the slopes and area of the distension-pressure loop curve decreased. The pulsatile distension and pressure waveforms were strongly altered in SHRLN. Maximal values were decreased and increased, respectively, and the waveform kinetics also differed. Thus the area under the curve adjusted to heart rate (AUC/ms) was calculated. Acute BP reductions were induced by diltiazem in SHR and SHRLN, to levels similar to those of WKY. In SHR, compliance, distensibility, stiffness index, and the ascending slope of the distension-pressure loop reached the values of WKY, whereas they were only partially improved in SHRLN. Aortic distension (maximal value and AUC/ms) and the area of the distension-pressure loop were improved in SHR, but not in SHRLN. These data confirm the aortic stiffening induced by nitric oxide reduction in SHR. They show that the ArtLab system analyzes aortic stiffness in rats, and that the aortic pulsatile distension waveform is a parameter strongly dependent on the vascular wall properties.

scholarly journals Exploring the GLP-1–GLP-1R axis in porcine pancreas and gastrointestinal tract in vivo by ex vivo autoradiography

2021 ◽  
Vol 9 (1) ◽  
pp. e002083
Author(s):  
Elin Manell ◽  
Emmi Puuvuori ◽  
Anna Svensson ◽  
Irina Velikyan ◽  
Gry Hulsart-Billström ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Pancreatic Beta Cells ◽  
Ex Vivo ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Porcine Pancreas ◽  
Positron Emission ◽  
Ex Vivo Autoradiography ◽  
Glucagon Like Peptide 1

IntroductionGlucagon-like peptide-1 (GLP-1) increases insulin secretion from pancreatic beta-cells and GLP-1 receptor (GLP-1R) agonists are widely used as treatment for type 2 diabetes mellitus. Studying occupancy of the GLP-1R in various tissues is challenging due to lack of quantitative, repeatable assessments of GLP-1R density. The present study aimed to describe the quantitative distribution of GLP-1Rs and occupancy by endogenous GLP-1 during oral glucose tolerance test (OGTT) in pigs, a species that is used in biomedical research to model humans.Research design and methodsGLP-1R distribution and occupancy were measured in pancreas and gastrointestinal tract by ex vivo autoradiography using the GLP-1R-specific radioligand 177Lu-exendin-4 in two groups of pigs, control or bottle-fed an oral glucose load. Positron emission tomography (PET) data from pigs injected with 68Ga-exendin-4 in a previous study were used to retrieve data on biodistribution of GLP-1R in the gastrointestinal tract.ResultsHigh homogenous uptake of 177Lu-exendin-4 was found in pancreas, and even higher uptake in areas of duodenum. Low uptake of 177Lu-exendin-4 was found in stomach, jejunum, ileum and colon. During OGTT, there was no increase in plasma GLP-1 concentrations and occupancy of GLP-1Rs was low. The ex vivo autoradiography results were highly consistent with to the biodistribution of 68Ga-exendin-4 in pigs scanned by PET.ConclusionWe identified areas with similarities as well as important differences regarding GLP-1R distribution and occupancy in pigs compared with humans. First, there was strong ligand binding in the exocrine pancreas in islets. Second, GLP-1 secretion during OGTT is minimal and GLP-1 might not be an important incretin in pigs under physiological conditions. These findings offer new insights on the relevance of porcine diabetes models.

scholarly journals RAGE antagonist peptide mitigates AGE-mediated endothelial hyperpermeability and accumulation of glycoxidation products in human ascending aortas and in a murine model of aortic aneurysm

2021 ◽  
Author(s):  
Chiara Camillo ◽  
Alexey Abramov ◽  
Philip M Allen ◽  
Estibaliz Castillero ◽  
Emilia Roberts ◽  
...  
Keyword(s):  
Aortic Stiffness ◽  
Aortic Wall ◽  
Ex Vivo ◽  
Endothelial Permeability ◽  
Ascending Aorta ◽  
Vascular Stiffness ◽  
Ecm Remodeling ◽  
Pressure Myograph

Background: Aortic dissection and aneurysm are the result of altered biomechanical forces associated with structural weakening of the aortic wall caused by genetic or acquired factors. Current guidelines recommend replacement of the ascending aorta when the diameter is >5.5 cm in tricuspid aortic valve patients. Aortopathies are associated with altered wall stress and stiffness as well as endothelial cell dysfunction and synthetic vascular smooth muscle cell (VSMC) phenotype. We reported that these mechanisms are mediated by glycoxidation products [Reactive oxygen species (ROS) and Advance Glycation End products (AGE)]. This study addresses the role of glycoxidation on endothelial function and AGE-mediated aortic stiffness. Hypothesis and aims: Here we investigate how circulating glycation products infiltrate the aortic wall via AGE-mediated endothelial hyperpermeability and contribute to both VSMC synthetic phenotype and extracellular matrix (ECM) remodeling in vivo and ex vivo. We also study how RAGE antagonist peptide (RAP) can rescue the effect of AGEs in vitro and in vivo in eNOS-/- vs WT mice. Methods and results: Human ascending aortas (n=30) were analyzed for AGE, ROS, and ECM markers. In vitro glycation was obtained by treating VSMC or human and murine aortas with glyoxal. Endothelial permeability was measured under glycation treatment. Vascular stiffness was measured by a pressure myograph comparing wild-type mice in the absence of presence of glyoxal. eNOS-/- mice, a model of increased endothelial permeability, were treated for 28 days with hyperlipidemic diet and Angiotensin II (1000ng/kg/min) with or without anti-glycation treatment (RAP 20mg/kg). Echo data of aortic diameter were collected. Murine vascular stiffness was measured by a pressure myograph (n=5/group). Glycoxidation products were detected in all human aortas independently of aortic diameter, with stronger accumulation on the lumen and the adventitia layer. AGEs increased endothelial permeability, induce synthetic phenotypic switch in human VSMCs, and inhibit cell migration. RAP pre-treatment rescue the effect of glyoxal on endothelial cells. Ex vivo glycation treatment of murine arteries impacted on ECM and increased stiffness. Aortic stiffness was higher in eNOS-/- vs WT mice. Ang II-mediated aortopathies results in aortic dilation, and AGE/ROS accumulation, which is rescued by RAGE antagonist peptide treatment of eNOS-/- mice. Conclusions: Glycoxidation reaction mediates EC permeability, VSMCs phenotype, and ECM remodeling leading to dysfunctional microstructure of the ascending aorta, altered vascular stiffness and increasing aortic susceptibility to dilation and rupture. Moreover, we show that RAP can mitigate AGE-mediated endothelial hyper-permeability in vitro and impact on ascending aneurysm in vivo

Abstract P200: Endothelial Estrogen Receptor Alpha Does Not Protect Female Mice Against Western Diet Induced Vascular Stiffness

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Camila Manrique ◽  
Guido Lastra ◽  
Dominic Haertling ◽  
Vincent DeMarco ◽  
Annayya Aroor ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Ex Vivo ◽  
Western Diet ◽  
Vascular Stiffness ◽  
Cell Stiffness ◽  
Whole Body ◽  
Receptor Alpha

Background: Women with obesity, insulin resistance and type 2 diabetes mellitus (T2D) lose the cardiovascular disease protection normally afforded by female sex hormones, but the underlying mechanism(s) remain unknown. Increases in vascular stiffness occur with aging, but conditions of insulin resistance such as obesity and T2D are characterized by accelerated development of this phenomenon. Under physiological conditions, vascular estrogen signaling via estrogen receptor alpha (ERα) increases endothelial bioavailable nitric oxide which decreases stiffness. Nevertheless, in conditions of insulin resistance, the effects of ERα signaling may be deleterious. Methods: We used a novel rodent model lacking ERα in the endothelial cells (ECERαKO). The genomic region encompassing exon 3 of the ERα gene was flanked by loxP sites. ECERαKO mice were generated by crossing ERα doubled floxed mice with Cad-Cre+ mice (VE-Cadherin promoter driving expression of Cre-recombinase). Female ECERαKO mice and littermates were fed a high fructose/high sucrose (Western diet - WD) for 8 weeks. The WD diet consisted of 60% fat and 20% sucrose. At the end of the intervention period, mice underwent in vivo and ex vivo assessment of vascular stiffness. Results: The absence of EC ERα did not impact whole body insulin sensitivity (examined by HOMA-IR). Females lacking the endothelial specific ERα had less vascular stiffness when assessed in vivo via aortic pulse wave velocity than the littermates fed with a WD (3.43 ± 0.184 m/s vs. 4.080 ± 0.172 m/s, p<0.05). Similarly, ex vivo evaluation of aortic endothelial cell stiffness using atomic force microscopy (AFM) revealed increased stiffness in the females with intact EC ERα when compared with ECERαKO females (1.91 ± 0.60 kPa vs. 13.09 ± 2.61 kPa ) (p<0.05). Resistant vessel (femoral artery) also revealed less stiffness (decreased modulus of elasticity) in ECERαKO mice fed a WD. Conclusion: Endothelial ERα does not protect females from vascular stiffness induced by a WD. Indeed, the present data suggest a predisposition toward protection of rodent lacking ERα in conditions of insulin resistance.

Abstract 543: Increased Aortic Pulse Wave Velocity in Type 2 Diabetic db/db Mice is Dependent on Blood Pressure

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Mircea Anghelescu ◽  
Keith J Gooch ◽  
Aaron J Trask
Keyword(s):  
Blood Pressure ◽  
Pulse Wave Velocity ◽  
Wave Velocity ◽  
Aortic Stiffness ◽  
Pulse Wave ◽  
Ex Vivo ◽  
Aortic Pulse Wave Velocity ◽  
Type 2 Diabetic

Pulse wave velocity (PWV) is the gold standard for in vivo aortic stiffness measurements but can be dependent upon blood pressure and/or heart rate. Previous studies from our and other labs have shown increased aortic PWV in type 2 diabetic db/db mice. Moreover, preliminary ex vivo pressure myography data from our lab has also shown a lack of increase in passive aortic stiffness, suggesting that increased PWV in vivo , and therefore, increased stiffness in db/db mice may be dependent upon other mechanisms. In this study, we tested the hypothesis that increased aortic pulse wave velocity measured in db/db mice in vivo is blood pressure dependent under anesthesia. 16-wk old normal Db/db (n=9) and type 2 diabetic db/db (n=5) mice were anesthetized with 2% isoflurane and instrumented with two 1.2F pressure-tip catheters: one inserted in the left carotid artery and advanced to the thoracic aorta, the other inserted into the left femoral artery and advanced into the abdominal aorta. Blood pressure was continuously recorded and PWV was calculated using the foot-to-foot method. A microcannula was inserted into the right jugular vein for the administration of drugs. After a stabilization period of 25-30 mins, baseline BPs and PWVs were measured, after which mice were infused with increasing doses of phenylephrine (Phe, 100-500 nmol/kg/min) and sodium nitroprusside (SNP, 100-500 nmol/kg/min) to increase and decrease blood pressure, respectively. At baseline (prior to the infusion of any drugs), mean arterial pressure and aortic PWV were significantly elevated in db/db mice under anesthesia (MAP; Db/db: 77±5 vs. db/db: 100±4 mmHg, p <0.05; PWV; Db/db: 0.31±0.01 vs. db/db: 0.35±0.01 cm/ms, p <0.05). The increase in aortic PWV in db/db mice at baseline was completely abrogated when measured at equivalent MAPs ranging from 40-120 mmHg during the Phe and SNP infusions ( p >0.05). In both Db/db and db/db mice, aortic PWV was significantly correlated with MAP (Db/db: r=0.94, p <0.001; db/db: r=0.97, p <0.0001). These data show that increased aortic PWV, and therefore increased aortic stiffness in db/db mice in vivo is dependent upon blood pressure.

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