Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

Souza‐Smith, Flavia M.; Katz, Paige S.; Trask, Aaron J.; Stewart, James A.; Lord, Kevin; Varner, Kurt J.; Vassallo, Dalton Valentim; Lucchesi, Pamela A.

doi:10.1371/journal.pone.0023337

Cited by 48 publications

(58 citation statements)

References 41 publications

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“…Our observation that femoral cross-sectional compliance at 40 mmHg was decreased in mice fed a WD further suggests that arterial wall stiffness was increased even at lower intravascular pressures. Compliance is a more sensitive measure of stiffness at lower pressures and takes into account the tubular form of the vessel (26,36,42). In addition, vascular wall components such as elastin and cytoskeletal structures rather than collagen are more important contributors to the elastic properties of the vessel at lower intravascular pressures (42,46).…”

Section: Discussionmentioning

confidence: 99%

“…Compliance is a more sensitive measure of stiffness at lower pressures and takes into account the tubular form of the vessel (26,36,42). In addition, vascular wall components such as elastin and cytoskeletal structures rather than collagen are more important contributors to the elastic properties of the vessel at lower intravascular pressures (42,46). Whether the increased femoral stiffness associated with WD feeding involved the structural changes we observed in the IEL remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…These data were subsequently used to calculate circumferential stress, strain, cross-sectional compliance, and modulus of elasticity curves for each group of vessels, as previously described (11,12,42).…”

Section: Animalsmentioning

confidence: 99%

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

Bender

Castorena‐Gonzalez

Garro

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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, 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-␤ (TGF-␤) 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-␤ signaling and IEL fenestrae remodeling as potential contributors to femoral artery stiffening in obesity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Bender

Castorena‐Gonzalez

Garro

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

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“…Diameter (m), wall thickness (m), pressure (mmHg), circumferential stress (dyne/cm 2 ), strain, and modulus of elasticity (dyne/cm 2 ) were calculated as previously described (25,33), and are expressed in absolute values. The circumferential stress was calculated at every pressure as i ϭ PiDi/(L,i ϩ R,i), where Pi is the intraluminal pressure, Di is the internal diameter, and, L,i and R,i are the left and right wall thicknesses obtained from the two-dimensional projection of the video caliper.…”

Section: Data Analysesmentioning

confidence: 99%

The obligatory role of the actin cytoskeleton on inward remodeling induced by dithiothreitol activation of endogenous transglutaminase in isolated arterioles

Castorena‐Gonzalez

Staiculescu

Foote

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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The obligatory role of the actin cytoskeleton on inward remodeling induced by dithiothreitol activation of endogenous transglutaminase in isolated arterioles. Am J Physiol Heart Circ Physiol 306: H485-H495, 2014. First published December 13, 2013 doi:10.1152/ajpheart.00557.2013.-Inward remodeling is the most prevalent structural change found in the resistance arteries and arterioles of hypertensive individuals. Separate studies have shown that the inward remodeling process requires transglutaminase activation and the polymerization of actin. Therefore, we hypothesize that inward remodeling induced via endogenous transglutaminase activation requires and depends on actin cytoskeletal structures. To test this hypothesis, isolated and cannulated rat cremaster arterioles were exposed to dithiothreitol (DTT) to activate endogenous transglutaminases. DTT induced concentration-dependent vasoconstriction that was suppressed by coincubation with cystamine or cytochalasin-D to inhibit tranglutaminase activity or actin polymerization, respectively. Prolonged (4 h) exposure to DTT caused arteriolar inward remodeling that was also blocked by the presence of cystamine or cytochalasin-D. DTT inwardly remodeled arterioles had reduced passive diameters, augmented wall thickness-to-lumen ratios and altered elastic characteristics that were reverted upon disruption of the actin cytoskeleton with mycalolide-B. In freshly isolated arterioles, exposure to mycalolide-B caused no changes in their passive diameters or their elastic characteristics. These results suggest that, in arterioles, the early stages of the inward remodeling process induced by prolonged endogenous transglutaminase activation require actin dynamics and depend on changes in actin cytoskeletal structures.hypertension; vasoconstriction; stiffness; elasticity; passive diameter INWARD REMODELING OF ARTERIOLES is the most prevalent structural change of the resistance vasculature observed in patients with hypertension and diabetes (14, 28). Its presence is associated with an increased risk for life-threatening cardiovascular events including stroke and myocardial infarction (22,27). However, despite its clinical importance, the mechanism(s) responsible for its development have not been completely elucidated.Cumulative evidence indicates that prolonged exposure to vasoconstrictor agonists causes inward remodeling of arterioles. Ex vivo, prolonged vasoconstriction induced by exposure of isolated arterioles to endothelin-1, angiotensin II, norepinephrine, or serum causes inward remodeling (4,5,19). In vivo, vasoconstriction also appears to be the primary stimulus causing inward remodeling in hypertension, as vasodilation and not a mere reduction in blood pressure is needed to prevent or revert inward remodeling in hypertensive individuals (8,21). The mechanism(s) responsible for inducing remodeling during prolonged vasoconstriction, however, remain elusive.A series of recent studies indicates that inward remodeling of arterioles requires transglutaminase activity. In 2005 B...

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“…Our recent work suggests that coronary microvascular remodeling in type 2 diabetic db/db mice differed from aortic and mesenteric resistance vessels 1,12 . To understand molecular mechanisms that account for these differences, in vitro studies using low passage VSMCs are necessary.…”

Section: Representative Resultsmentioning

confidence: 95%

Isolation of Murine Coronary Vascular Smooth Muscle Cells

Husarek

Zhang

McCallinhart

et al. 2016

JoVE

Self Cite

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While the isolation and culture of vascular smooth muscle cells (VSMCs) from large vessels is well established, we sought to isolate and culture VSMCs from the coronary circulation. Hearts with intact aortic arches were removed and perfused via retrograde Langendorff with digestion solution containing 300 Units/ml of collagenase type II, 0.1 mg/ml soybean trypsin inhibitor and 1 M CaCl 2 . The perfusates were collected at 15 min intervals for 90 min, pelleted by centrifugation, resuspended in plating media, and plated on tissue culture dishes. VSMCs were characterized by presence of SM22α, α-SMA, and vimentin. One of the main advantages of using this technique is the ability to isolate VSMCs from the coronary circulation of mice. Although the small number of cells obtained can limit some of the applications for which the cells can be utilized, isolated coronary VSMCs can be used in a variety of well-established cell culture techniques and assays. Studies investigating VSMCs from genetically modified mice can provide further information about structure-function and signaling processes associated with vascular pathologies. Video LinkThe video component of this article can be found at

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Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

Cited by 48 publications

References 41 publications

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

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

The obligatory role of the actin cytoskeleton on inward remodeling induced by dithiothreitol activation of endogenous transglutaminase in isolated arterioles

Isolation of Murine Coronary Vascular Smooth Muscle Cells

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