Mechanical Strength of the Isolated Carotid Artery in SHR

Abstract-Hypertension and aging are associated with large artery structural remodeling and stiffening, which are known to increase cardiovascular risk. Relaxin is a peptide hormone with potent antifibrotic action in multiple organs. Although relaxin is able to reduce peripheral vascular resistance and improve arterial compliance in rats, it remains unclear whether the improvement in compliance is indirectly attributed to a vasodilatory action or whether relaxin is able to reverse arterial remodeling and stiffening directly in aged hypertensive animals. Senescent spontaneously hypertensive rats (17 months old) were treated with relaxin for 2 weeks (0.5 mg/kg per day) followed by a 1-week washout period.We determined large artery compliance using in vivo and in vitro techniques and quantified arterial remodeling by morphological and chemical means. Relaxin therapy significantly reversed aortic remodeling (ie, increases in vessel size, wall thickness, and collagen content) and improved arterial compliance, effects independent of its vasodilatory action. In relaxin-treated spontaneously hypertensive rats, arterial collagen content showed a greater reduction (Ϫ31%; PϽ0.05) than that of elastin (Ϫ8%) 4 Several studies have provided strong evidence for relaxin as a potent vasodilator in vitro and in vivo. [5][6][7] The signaling mechanisms involve stimulating nitric oxidase synthases or endothelin-␤-mediated vasodilatory signaling 8 and antagonizing vasoconstriction induced by angiotensin II, endothelin 1, and catecholamines. 9 Conrad and colleagues 7,10 showed that treatment with relaxin either acutely or for a period of 10 days increased large artery compliance and cardiac output without a change in blood pressure in normotensive or hypertensive rats.Another unique feature of relaxin is its potent antifibrotic action. 11,12 In relaxin knockout mice, fibrosis occurs with aging in multiple organs. 11,[13][14][15] Conversely, administration of relaxin for 2 weeks effectively reversed organ fibrosis in relaxin knockout mice or other models of cardiac fibrosis, 11 including spontaneously hypertensive rats (SHR) showing reduced cardiac and renal fibrosis by relaxin therapy for 2 weeks. 16 Relaxin achieves its antifibrotic action through multiple mechanisms involving suppression of collagen synthesis via inhibiting fibroblast activation/proliferation and promotion of collagen degradation through activating matrix metalloproteinases. 11 Previous studies on the cardiovascular properties of relaxin have focused on its antifibrotic actions in the heart or blood pressure-lowering effect, 2,7 and it remains unknown whether chronic relaxin treatment in hypertensive models is able to reverse remodeling of large arteries. Progress in this area would advance our understanding of the therapeutic potential of relaxin. In the current study, we have addressed the hypothesis that relaxin therapy in SHRs is able to reverse large artery remodeling with accompanied improvement in arterial compliance. To make our findings more applicab...

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“…The external diameter was measured, and dimension/ pressure and pressure/distensibility curves were constructed. 7,19,20 …”

Section: Measurement Of Arterial Compliance Ex Vivomentioning

confidence: 99%

Relaxin Therapy Reverses Large Artery Remodeling and Improves Arterial Compliance in Senescent Spontaneously Hypertensive Rats

Chakravorty

Bathgate

et al. 2010

Hypertension

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“…The mechanical strength of the intact CA was characterized by determining the in vitro intraluminal pressure required to induce vascular wall rupture as described previously. 23 …”

Section: In Vivo Mechanical Propertiesmentioning

confidence: 99%

Modifications of Arterial Phenotype in Response to Amine Oxidase Inhibition by Semicarbazide

Mercier

Hadri²,

Osborne-Pellegrin³

et al. 2007

Hypertension

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Abstract-Semicarbazide-sensitive amine oxidase (SSAO)-deficient mice present no alteration in elastin cross-linking processes and carotid mechanical properties. In contrast, previous studies have shown that SSAO inhibitors induced marked anomalies in arterial structure and function. The aim of the present study was to examine the effect of semicarbazide (SCZ), an efficient SSAO inhibitor, on the arterial phenotype of the carotid artery in relation to modulation of SSAO and lysyl oxidase activities in growing rats. We first show that after 6 weeks of SCZ treatment (100 mg/kg per day), SSAO activity was reduced by 90%, whereas lysyl oxidase activity was only partially inhibited (Ͻ60%) in carotid artery, compared with controls. There was significant growth inhibition and no difference in mean arterial pressure but an increase in pulse pressure with a smaller arterial diameter in SCZ-treated rats. SCZ decreased aortic insoluble elastin without a change in total collagen. In addition, extracellular proteins other than insoluble elastin and collagen were increased in SCZ-treated rats. All of the elastic lamellae presented globular masses along their periphery, and focal disorganization was observed in the ascending aorta. Carotid artery mechanical strength was lower in SCZ-treated rats, and the elastic modulus-wall stress curve was shifted leftward compared with controls, indicating increased stiffness. Thus, SCZ modifies arterial geometry and mechanical properties, alters elastic fiber structure, and reduces the content of cross-linked elastin. Because these abnormalities are essentially absent in SSAO-deficient mice, our results suggest that lysyl oxidase inhibition is responsible for the major part of the vascular phenotype of SCZ-treated rats. Key Words: SSAO Ⅲ carotid artery Ⅲ LOX Ⅲ arterial stiffness Ⅲ elastin T he maturation of elastin and collagen is crucial for the organization of the extracellular matrix (ECM) and to provide functional elasticity and tensile strength of the arterial wall. It is generally considered that the formation of intramolecular and extramolecular cross-links of both elastin and collagen is mediated by lysyl oxidase (LOX). LOX is a carbonyl-dependent copper enzyme, expressed, synthesized, and secreted by vascular smooth muscle cells. 1 Many years ago, Lalich 2 showed that the pharmacological inhibition of LOX with ␤-aminopropionitrile (〉APN) induced aortic ruptures and aneurysms in rat. Mice lacking LOX do not deposit normal elastic fibers and develop aortic aneurysms. 3,4 Another copper-containing amine oxidase, semicarbazidesensitive amine oxidase (SSAO), also called vascular adhesion protein-1, is highly expressed in the plasma membrane of vascular smooth muscle cells of the aortic media. [5][6][7] The exact roles of SSAO in vascular wall function remain unknown. Several previous results support the hypothesis that SSAO may be involved in vascular smooth muscle cell differentiation, organization of the ECM, 8 and regulation of vascular tone. 9 -12 Langford et al 11 have shown that p...

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“…41 Another study identified intimal layer subfailures in rat carotid arteries under circumferential loading, although mechanics were not quantified. 11 The most appropriate methodology to identify and quantify internal layer subfailures is to open the vessel, exposing the intimal side prior to longitudinal failure testing. 54 This protocol permits synchronous identification of subfailures using videography and mechanical loading data.…”

Section: Investigation Of Vessel Mechanicsmentioning

confidence: 99%

Biomechanical Characterization of Internal Layer Subfailure in Blunt Arterial Injury

et al. 2006

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Blunt carotid artery injuries occur in 0.3% of blunt injured patients and may lead to devastating neurological consequences. However, arterial mechanics leading to internal layer subfailure have not been quantified. Twenty-two human carotid artery segments and 18 porcine thoracic aorta segments were opened to expose the intimal side and longitudinally distracted to failure. Porcine aortas were a geometrically accurate model of human carotid arteries. Internal layer subfailures were identified using videography and correlated with mechanical data. Ninety-three percent (93%) of vessels demonstrated subfailure prior to catastrophic failure. All subfailures occurred on the intimal surface. Initial subfailure occurred at 79% of the stress and 85% of the strain to catastrophic failure in younger porcine specimens, compared to 44% and 60%, respectively, in older human specimens. In most cases, multiple subfailures occurred prior to catastrophic failure. Due to limitations in human specimen quality (age, prior storage), young and fresh porcine aorta specimens are likely a more accurate model of clinical blunt carotid artery injuries. Present results indicate that vessels are acutely capable of maintaining physiologic function following initial subfailure. Delayed symptomatology commonly associated with blunt arterial injuries is explained by this mechanics-based and experimentally quantified onset of subcatastrophic failure.

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Mechanical Strength of the Isolated Carotid Artery in SHR

Cited by 32 publications

References 34 publications

Relaxin Therapy Reverses Large Artery Remodeling and Improves Arterial Compliance in Senescent Spontaneously Hypertensive Rats

Relaxin Therapy Reverses Large Artery Remodeling and Improves Arterial Compliance in Senescent Spontaneously Hypertensive Rats

Modifications of Arterial Phenotype in Response to Amine Oxidase Inhibition by Semicarbazide

Biomechanical Characterization of Internal Layer Subfailure in Blunt Arterial Injury

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