Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization

Foote, Christopher; Castorena‐Gonzalez, Jorge A.; Staiculescu, Marius C.; Clifford, Philip S.; Hill, Michael A.; Meininger, Gerald A.; Martinez‐Lemus, Luis A.

doi:10.1152/ajpheart.00666.2015

Cited by 14 publications

(5 citation statements)

References 51 publications

(65 reference statements)

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“…Fourth, findings from the ex vivo treatment of arteries or cells with adropin for 24 hours suggest that adropin-induced de-stiffening effects can occur rather quickly. The acute nature of these adropin effects is consistent with the idea that cytoskeletal remodeling can occur rapidly (i.e., within minutes/hours) (207,(221)(222)(223); nevertheless, time course studies are needed to establish the kinetics of these changes. Fifth, follow-up telemetry studies are needed to determine if the observed changes in arterial stiffness in our mouse model of adropin deficiency and/or adropin treatment are associated with, or independent of, changes in blood pressure.…”

Section: Discussionsupporting

confidence: 66%

Role of adropin in arterial stiffening associated with obesity and type 2 diabetes

Jurrissen

Ramirez‐Perez

Cabral-Amador

et al. 2022

American Journal of Physiology-Heart and Circulatory Physiology

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Adropin is a peptide largely secreted by the liver and known to regulate energy homeostasis; however, it also exerts cardiovascular effects. Herein, we tested the hypothesis that low circulating levels of adropin in obesity and type 2 diabetes (T2D) contribute to arterial stiffening. In support of this hypothesis, we report that obesity and T2D is associated with reduced levels of adropin (in liver and plasma) and increased arterial stiffness in mice and humans. Establishing causation, we show that mesenteric arteries from adropin knockout mice are also stiffer, relative to arteries from wild-type counterparts, thus recapitulating the stiffening phenotype observed in T2D db/db mice. Given the above, we performed a set of follow-up experiments, in which we found that: 1) exposure of endothelial cells or isolated mesenteric arteries from db/db mice to adropin reduces filamentous actin (F-actin) stress fibers and stiffness; 2) adropin-induced reduction of F-actin and stiffness in endothelial cells and db/db mesenteric arteries is abrogated by inhibition of nitric oxide (NO) synthase; and 3) stimulation of smooth muscle cells or db/db mesenteric arteries with a NO mimetic reduces stiffness. Last, we demonstrated that in vivo treatment of db/db mice with adropin for four weeks reduces stiffness in mesenteric arteries. Collectively, these findings indicate that adropin can regulate arterial stiffness, likely via endothelial-derived NO, and thus support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D.

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Section: Discussionsupporting

confidence: 66%

Role of adropin in arterial stiffening associated with obesity and type 2 diabetes

Jurrissen

Ramirez‐Perez

Cabral-Amador

et al. 2022

American Journal of Physiology-Heart and Circulatory Physiology

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“…While progress has been made in following actin polymerization in small blood vessels (Foote et al . ), this is not yet suitable for measurement of depolymerization which would have been required for the present study.…”

Section: Discussionmentioning

confidence: 95%

Mechanical activation of angiotensin II type 1 receptors causes actin remodelling and myogenic responsiveness in skeletal muscle arterioles

Hong

Zhao

Hong

et al. 2016

The Journal of Physiology

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The G protein-coupled angiotensin II type 1 receptor (AT R) has been shown to be activated by mechanical stimuli. In the vascular system, evidence supports the AT R being a mechanosensor that contributes to arteriolar myogenic constriction. The aim of this study was to determine if AT R mechanoactivation affects myogenic constriction in skeletal muscle arterioles and to determine underlying cellular mechanisms. Using pressure myography to study rat isolated first-order cremaster muscle arterioles the AT R inhibitor candesartan (10 -10 m) showed partial but concentration-dependent inhibition of myogenic reactivity. Inhibition was demonstrated by a rightward shift in the pressure-diameter relationship over the intraluminal pressure range, 30-110 mmHg. Pressure-induced changes in global vascular smooth muscle intracellular Ca (using Fura-2) were similar in the absence or presence of candesartan, indicating that AT R-mediated myogenic constriction relies on Ca -independent downstream signalling. The diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG) reversed the inhibitory effect of candesartan, while this rescue effect was prevented by the protein kinase C (PKC) inhibitor GF 109203X. Both candesartan and PKC inhibition caused increased G-actin levels, as determined by Western blotting of vessel lysates, supporting involvement of cytoskeletal remodelling. At the single vascular smooth muscle cell level, atomic force microscopy showed that cell swelling (stretch) with hypotonic buffer also caused thickening of cortical actin fibres and this was blocked by candesartan. Collectively, the present studies support growing evidence for novel modes of activation of the AT R in arterioles and suggest that mechanically activated AT R generates diacylglycerol, which in turn activates PKC which induces the actin cytoskeleton reorganization that is required for pressure-induced vasoconstriction.

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“…However, this is the first report showing that diet induced obesity is associated with enhanced EnNaC expression, and that this is prevented XO inhibition. The activation of EnNaC results in polymerization of G- to F-actin [30]. This results in decreased flow-mediated NO production due to disruption of the endothelial glycocalyx (i.e., surface layer comprising a complex of glycoproteins located on the luminal surface of EC) and its interaction with endothelial nitric oxide synthase (eNOS) during flow-mediated vasodilation [31].…”

Section: Discussionmentioning

confidence: 99%

Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice

et al. 2017

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Objective Aortic vascular stiffness has been implicated in the development of cardiovascular disease (CVD) and chronic kidney disease (CKD) in obese individuals. However, the mechanism promoting these adverse effects are unclear. In this context, promotion of obesity through consumption of a western diet (WD) high in fat and fructose leads to excess circulating uric acid. There is accumulating data implicating elevated uric acid in the promotion of CVD and CKD. Accordingly, we hypothesized that xanthine oxidase inhibition with allopurinol would prevent a rise in vascular stiffness and proteinuria in a translationally relevant model of WD-induced obesity. Materials/Methods Four-week-old C57BL6/J male mice were fed a WD with excess fat (46%) and fructose (17.5%) with or without allopurinol (125mg/L in drinking water) for 16 weeks. Aortic endothelial and extracellular matrix/vascular smooth muscle stiffness was evaluated by atomic force microscopy. Aortic XO activity, 3-nitrotyrosine and aortic endothelial sodium channel (EnNaC) expression were evaluated along with aortic expression of inflammatory markers. In the kidney, expression of toll like receptor 4 (TLR4) and fibronectin were assessed along with evaluation of proteinuria. Results XO inhibition significantly attenuated WD-induced increases in plasma uric acid, vascular XO activity and oxidative stress, in concert with reductions in proteinuria. Further, XO inhibition prevented WD-induced increases in aortic EnNaC expression and associated endothelial and subendothelial stiffness. XO inhibition also reduced vascular pro-inflammatory and maladaptive immune responses induced by consumption of a WD. XO inhibition also decreased WD-induced increases in renal TLR4 and fibronectin that associated proteinuria. Conclusions Consumption of a WD leads to elevations in plasma uric acid, increased vascular XO activity, oxidative stress, vascular stiffness, and proteinuria all of which are attenuated with allopurinol administration.

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Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization

Cited by 14 publications

References 51 publications

Role of adropin in arterial stiffening associated with obesity and type 2 diabetes

Role of adropin in arterial stiffening associated with obesity and type 2 diabetes

Mechanical activation of angiotensin II type 1 receptors causes actin remodelling and myogenic responsiveness in skeletal muscle arterioles

Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice

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