Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency

Faury, Gilles; Pezet, Mylène; Knutsen, Russell H.; Boyle, Walter A.; Heximer, Scott P.; McLean, Sean E.; Minkes, Robert K.; Blumer, Kendall J.; Kovács, Attila; Kelly, Daniel P.; Li, Dean Y.; Starcher, Barry; Mecham, Robert P.

doi:10.1172/jci19028

Cited by 223 publications

(209 citation statements)

References 44 publications

Supporting

Mentioning

187

Contrasting

Unclassified

Order By: Relevance

“…Vessels were carefully cleaned of adipose tissue, cannulated, and mounted onto a pressure arteriograph, placed onto a microscope with video monitoring. Mechanistic study was performed, as previously described 26, 27, 28. Circumferential wall stress (representative of all forces that are circumferentially applied on each small portion of the vessel wall) and incremental elastic modulus (Einc) (representative of wall stiffness) were calculated from the inner and outer diameters at transluminal pressures ranging from 0 to 175 mm Hg, according to the formulas given by Gibbons and Shadwick 29…”

Section: Methodsmentioning

confidence: 99%

“…Responses to PE are presented as the percentage decrease in inner diameter (ID), compared with the control diameter at 75 mm Hg before PE application: PE‐induced contraction (%)=100×(ID control −ID PE )/ID control . Responses to Ach are presented as the percentage restoration of the ID after PE‐induced constriction: Ach‐induced vasodilation (%)=100×(ID Ach+PE −ID PE )/(ID control −ID PE ) 27, 28…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Nonmuscle Myosin Light Chain Kinase: A Key Player in Intermittent Hypoxia‐Induced Vascular Alterations

Arnaud

Bouyon

Recoquillon

et al. 2018

JAHA

Self Cite

View full text Add to dashboard Cite

BackgroundObstructive sleep apnea is characterized by repetitive pharyngeal collapses during sleep, leading to intermittent hypoxia (IH), the main contributor of obstructive sleep apnea–related cardiovascular morbidity. In patients and rodents with obstructive sleep apnea exposed to IH, vascular inflammation and remodeling, endothelial dysfunction, and circulating inflammatory markers are linked with IH severity. The nonmuscle myosin light chain kinase (nmMLCK) isoform contributes to vascular inflammation and oxidative stress in different cardiovascular and inflammatory diseases. Thus, in the present study, we hypothesized that nmMLCK plays a key role in the IH‐induced vascular dysfunctions and inflammatory remodeling.Methods and ResultsTwelve‐week‐old nmMLCK +/+ or nmMLCK −/− mice were exposed to 14‐day IH or normoxia. IH was associated with functional alterations characterized by an elevation of arterial blood pressure and stiffness and perturbations of NO signaling. IH caused endothelial barrier dysfunction (ie, reduced transendothelial resistance in vitro) and induced vascular oxidative stress associated with an inflammatory remodeling, characterized by an increased intima‐media thickness and an increased expression and activity of inflammatory markers, such as interferon‐γ and nuclear factor‐κB, in the vascular wall. Interestingly, nmMLCK deletion prevented all IH‐induced functional and structural alterations, including the restoration of NO signaling, correction of endothelial barrier integrity, and reduction of both oxidative stress and associated inflammatory response.ConclusionsnmMLCK is a key mechanism in IH‐induced vascular oxidative stress and inflammation and both functional and structural remodeling.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Nonmuscle Myosin Light Chain Kinase: A Key Player in Intermittent Hypoxia‐Induced Vascular Alterations

Arnaud

Bouyon

Recoquillon

et al. 2018

JAHA

Self Cite

View full text Add to dashboard Cite

show abstract

“…data]. Life expectancy is also normal for Eln +/– mice [26]. As described previously, tail clipping was performed within 4 weeks of birth to determine the genotype of each mouse using PCR and appropriate primers [19,20].…”

Section: Methodsmentioning

confidence: 99%

“…In humans, this results in an increased risk of obstructive vascular disease. Further research with Eln +/– mice found the animals to be stably hypertensive from birth [26] with slightly smaller and stiffer arteries [27] compared to wild-type littermates (WT- Eln ). Hypertension and an increase in the number of lamellar units, both characteristics of human elastin arteriopathy, may be developmental adaptations to normalize vascular perfusion and circumferential vessel strain.…”

Section: Introductionmentioning

confidence: 99%

Induced Chromosome Deletion in a Williams-Beuren Syndrome Mouse Model Causes Cardiovascular Abnormalities

Goergen

Francke

et al. 2010

J Vasc Res

View full text Add to dashboard Cite

Aims: The Williams-Beuren syndrome (WBS) is a genetic disorder caused by a heterozygous ∼1.5-Mb deletion. The aim of this study was to determine how the genetic changes in a Wbs mouse model alter Eln expression, blood pressure, vessel structure, and abdominal aortic wall dynamics in vivo. Methods: Elastin (ELN) transcript levels were quantified by qRT-PCR and blood pressure was measured with a tail cuff system. M-mode ultrasound was used to track pulsatile abdominal aortic wall motion. Aortas were sectioned and stained to determine medial lamellar structure. Results: ELN transcript levels were reduced by 38–41% in Wbs mice lacking one copy of the ELN gene. These mice also had a 10–20% increase in mean blood pressure and significantly reduced circumferential cyclic strain (p < 0.001). Finally, histological sections showed disorganized and fragmented elastin sheets in Wbs mice, but not the characteristic increase in lamellar units seen in Eln^+/– mice. Conclusions: The deletion of Eln in this Wbs mouse model results in lower gene expression, hypertension, reduced cyclic strain, and fragmented elastin sheets. The observation that the number of medial lamellar units is normal in Wbs deletion mice, which is in contrast to Eln^+/– mice, suggests other genes may be involved in vascular development.

show abstract

“…We have shown that mice with about 60% of normal elastin levels (Elnþ/2) are able to adapt to develop suitable cardiovascular function for a normal lifespan. The adaptations include increased blood pressure, decreased arterial diameter and wall thickness, increased arterial length, increased lamellar units, decreased arterial compliance and similar arterial stress -strain relationships [4][5][6]. Many of the adaptations occur early in maturation and are measurable by postnatal day (P) 7 [7,8].…”

Section: Introductionmentioning

confidence: 99%

Mechanical factors direct mouse aortic remodelling during early maturation

Cheng

Kim

et al. 2015

J. R. Soc. Interface.

Self Cite

View full text Add to dashboard Cite

Numerous diseases have been linked to genetic mutations that lead to reduced amounts or disorganization of arterial elastic fibres. Previous work has shown that mice with reduced amounts of elastin (Elnþ/2) are able to live a normal lifespan through cardiovascular adaptations, including changes in haemodynamic stresses, arterial geometry and arterial wall mechanics. It is not known if the timeline and presence of these adaptations are consistent in other mouse models of elastic fibre disease, such as those caused by the absence of fibulin-5 expression (Fbln52/2). Adult Fbln52/2 mice have disorganized elastic fibres, decreased arterial compliance and high blood pressure. We examined mechanical behaviour of the aorta in Fbln52/2 mice through early maturation when the elastic fibres are being assembled. We found that the physiologic circumferential stretch, stress and modulus of Fbln52/2 aorta are maintained near wild-type levels. Constitutive modelling suggests that elastin contributions to the total stress are decreased, whereas collagen contributions are increased. Understanding how collagen fibre structure and mechanics compensate for defective elastic fibres to meet the mechanical requirements of the maturing aorta may help to better understand arterial remodelling in human elastinopathies.

show abstract

Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency

Cited by 223 publications

References 44 publications

Nonmuscle Myosin Light Chain Kinase: A Key Player in Intermittent Hypoxia‐Induced Vascular Alterations

Nonmuscle Myosin Light Chain Kinase: A Key Player in Intermittent Hypoxia‐Induced Vascular Alterations

Induced Chromosome Deletion in a Williams-Beuren Syndrome Mouse Model Causes Cardiovascular Abnormalities

Mechanical factors direct mouse aortic remodelling during early maturation

Contact Info

Product

Resources

About