Mylène Pezet

Developmental adaptation of the mouse cardiovascular system to elastin haploinsufficiency

Supravalvular aortic stenosis is an autosomal-dominant disease of elastin (Eln) insufficiency caused by loss-of-function mutations or gene deletion. Recently, we have modeled this disease in mice (Eln+/-) and found that Eln haploinsufficiency results in unexpected changes in cardiovascular hemodynamics and arterial wall structure. Eln+/- animals were found to be stably hypertensive from birth, with a mean arterial pressure 25-30 mmHg higher than their wild-type counterparts. The animals have only moderate cardiac hypertrophy and live a normal life span with no overt signs of degenerative vascular disease. Examination of arterial mechanical properties showed that the inner diameters of Eln+/- arteries were generally smaller than wild-type arteries at any given intravascular pressure. Because the Eln+/- mouse is hypertensive, however, the effective arterial working diameter is comparable to that of the normotensive wild-type animal. Physiological studies indicate a role for the renin-angiotensin system in maintaining the hypertensive state. The association of hypertension with elastin haploinsufficiency in humans and mice strongly suggests that elastin and other proteins of the elastic fiber should be considered as causal genes for essential hypertension.

Elastin haploinsufficiency induces alternative aging processes in the aorta

Elastin, the main component of elastic fibers, is synthesized only in early life and provides the blood vessels with their elastic properties. With aging, elastin is progressively degraded, leading to arterial enlargement, stiffening, and dysfunction. Also, elastin is a key regulator of vascular smooth muscle cell proliferation and migration during development since heterozygous mutations in its gene (Eln) are responsible for a severe obstructive vascular disease, supravalvular aortic stenosis, isolated or associated to Williams syndrome. Here, we have studied whether early elastin synthesis could also influence the aging processes, by comparing the structure and function of ascending aorta from 6- and 24-month-old Eln+/- and Eln+/+ mice. Eln+/- animals have high blood pressure and arteries with smaller diameters and more rigid walls containing additional although thinner elastic lamellas. Nevertheless, longevity of these animals is unaffected. In young adult Eln+/- mice, some features resemble vascular aging of wild-type animals: cardiac hypertrophy, loss of elasticity of the arterial wall through enhanced fragmentation of the elastic fibers, and extracellular matrix accumulation in the aortic wall, in particular in the intima. In Eln+/- animals, we also observed an age-dependent alteration of endothelial vasorelaxant function. On the contrary, Eln+/- mice were protected from several classical consequences of aging visible in aged Eln+/+ mice, such as arterial wall thickening and alteration of alpha(1)-adrenoceptor-mediated vasoconstriction. Our results suggest that early elastin expression and organization modify arterial aging through their impact on both vascular cell physiology and structure and mechanics of blood vessels.

Fibrillin-1 genetic deficiency leads to pathological ageing of arteries in mice†

Fibrillin‐1, the major component of extracellular microfibrils that associate with insoluble elastin in elastic fibres, is mainly synthesized during development and postnatal growth and is believed to guide elastogenesis. Mutations in the fibrillin‐1 gene cause Marfan syndrome, a multisystem disorder characterized by aortic aneurysms and dissections. The recent finding that early deficiency of elastin modifies vascular ageing has raised the possibility that fibrillin‐1 deficiency could also contribute to late‐onset pathology of vascular remodelling. To address this question, we examined cardiovascular function in 3‐week‐old, 6‐month‐old, and 24‐month‐old mice that are heterozygous for a hypomorphic structural mutation of fibrillin‐1 (Fbn1

Potassium Channel Openers Increase Aortic Elastic Fiber Formation and Reverse the Genetically Determined Elastin Deficit in the BN Rat

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Cell cycle disruption and apoptosis as mechanisms of toxicity of organochlorines in Zea mays roots.

mice). Our results indicate that Fbn1

Comparative differential proteomic profiles of nonfailing and failing hearts after in vivo thoracic aortic constriction in mice overexpressing FKBP12.6

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Heat shock factor 1 promotes TERRA transcription and telomere protection upon heat stress

mice, particularly those that are 24 months old, are slightly more hypotensive than wild‐type littermates. Additionally, aneurysm and aortic insufficiency were more frequently observed in ageing Fbn1

FKBP12.6 overexpression does not protect against remodelling after myocardial infarction

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Gender-Specific Potential Inhibitory Role of Ca2+/Calmodulin Dependent Protein Kinase Phosphatase (CaMKP) in Pressure-Overloaded Mouse Heart

mice than in the wild‐type counterparts. We also noted substantial fragmentation and decreased number of elastic lamellae in the aortic wall of Fbn1

0204: Proteome-wide sex-related differences in response to mouse thoracic aortic constriction: molecular bio-signature of failing hearts

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