Background: Maternal obesity pre-programme offspring to develop obesity and associated cardiovascular disease later in life. In health, perivascular adipose tissue (PVAT) reduces vascular contractility, an effect lost in obesity and during pregnancy. However, neither the effect of obesity during pregnancy on PVAT function in the mothers nor the possible epigenetic effect in the offspring is known. This study sought to identify detrimental vascular changes in post-partum dams and their offspring resulting from maternal obesity. Methods: Six-eight week old female Sprague-Dawley rats were fed a 10% fat (control) or 45% fat diet (HFD) for 12 weeks before mating, throughout pregnancy and during lactation. Offspring received the control diet until sacrifice at 12 (12wo) or 24 (24wo) weeks of age. PVAT-denuded (with or without exogenous PVAT) and PVAT-intact mesenteric arteries from mothers and pups were mounted on a wire myograph and vascular contractility to thromboxane A2 agonist (U46619) and norepinephrine was assessed in the presence of pharmacological tools. Western blotting, immunoprecipitation and an AMPK activity assay were used to detect any changes in the PVAT environment. Results: Offspring of obese mothers were overweight, mildly hypertensive and insulin resistant. Contractions in PVAT-denuded arteries from HFD dams and their offspring were reduced by a mechanism involving increased protein O-GlcNAcylation. PVAT exerted an anti-contractile effect in vessels from control offspring and their mothers through the release of relaxant factors, which included nitric oxide (NO). The anti-contractile effect of PVAT was lost in HFD offspring due to reduced NO bioavailability and increased O-GlcNAcylation, which lead to decreased AMPK activity within PVAT. However, simultaneous AMPK activation within PVAT partially restored the anti-contractile capability in HFD offspring. Reduced NO bioavailability also lead to PVAT dysfunction in HFD mothers. Conclusions: Elevated insulin levels in the HFD offspring may lead to enhanced glucose uptake and increased protein O-GlcNAcylation, which contributes to the PVAT dysfunction in HFD offspring. The PVAT dysfunction, which is associated with reduced NO bioavailability in HFD mothers and their offspring may be the result of reduced AMPK phosphorylation of nitric oxide synthase within PVAT.

Le syndrome d'apnée obstructive du sommeil (SAOS), est une maladie chronique qui se caractérise par des interruptions répétées de la respiration durant le sommeil en raison de la fermeture temporaire des voies aériennes supérieures. L'hypoxie intermittente chronique (HI) résultante de cette fermeture transitoire des voies aériennes supérieures, constitue l’une des conséquences majeures du SAOS, et elle est la responsable de la plupart des complications liées à cette pathologie, dont nous citons: l’hypertension artérielle, l’infarctus de myocarde et plus généralement le remodelage cardiovasculaire.D’autre part, l’entrainement physique intensif(EI)est bien connu d’avoir des bénéfices sur le système cardiovasculaire, d’où nous avons poser l’hypothèse que l’EI peut inverser les effets délétères de l’HI sur la réactivité et le remodelage vasculaire ainsi que sur la signalisation calcique intracellulaire dans les cellules musculaires.Pour répondre à cette question, nous avons choisi le rat comme modèle animal, pour étudier l’effet potentiel de l'EI dans la prévention et l’inversion des effets délétères de (HI) en termes de réactivité et signalisation calcique dans les tissues musculaires.Des rats ont été exposés durant 21 jours à l’hypoxie intermittente dans des cages spécialement équipées pour maintenir un flux d’air alternant entre 21% et 5% de PO2 dans les cages contenant les rats hypoxique et a 21% de PO2 dans les cages contenant les rats contrôles. Durant les deux dernières semaines d’exposition à l’HI, un groupe des rats hypoxiques et un des rats normoxiques ont subi des sessions d'EI en courant sur un tapis roulant avec une vitesse allant de 16m/min jusqu'à 30 m/min.Les paramètres physiologiques ont été mesurés (Pression artérielle, fréquence cardiaque, hématocrites), l’aorte a été prélevé pour étudier la réactivité vasculaire, les cellules musculaires lisses de l’aorte ont été ensuite prélevés et cultivées pour étudier la signalisation calcique par microscopie à EPIfluorescence. Finalement les gènes codant pour les médiateurs de la signalisation calcique : RyR1, RyR2 RyR3, (ryanodine receptors), TRPV4 (transient receptor potential channel), SERCA1, SERCA2 (Sarco/Endoplasmic Reticulum Ca2+ -ATPase) et IP3R1 (Inositol 1,4,5-Trisphosphate Receptor) dans différentes tissues vasculaires et squelettiques ont été étudiés au niveau moléculaire par Q-PCR et Western Blot.Nos résultats montrent que l'HI induit une augmentation significative de pression artérielle et de l’hématocrite et une diminution dans la relaxation de l'aorte induite par l'acétylcholine pré contractée par la phénylnephrine. Ceci est conforme à notre observation selon laquelle HI augmente le niveau de calcium intracellulaire dans le muscle lisse aortique cultivé. D'autre part, l'EI induit une diminution significative de l’hématocrite et de la vasoconstriction aortique induite par la phénylnephrine et l'endothélie-1, conformément à l'observation que l'EI réduit la différence HI-N dans la réponse calcique. A l’échelle moléculaire, HI induit une augmentation significative de l'expression de RyR1, RyR2, RyR3, SERCA1, SERCA2, TRPV4 et IP3R1 au niveau de l'ARNm dans les tissus de tous les groupes, avec une plus grande quantité de RyR1,RyR2,et RyR3 dans les tissus HI des muscles lisses (principalement dans l'aorte thoracique et abdominale) et le SERCA1 (9 fois plus haut dans les tissus IH) et le SERCA2 (10 fois plus élevé dans les tissus HI) dans les muscles squelette (Gastrocnemius, plantaris et soléus). De plus, HI induit une augmentation significative de RYR1, RYR2 et TRPV4 au niveau protéique dans l'aorte thoracique et abdominale; et l'EI réduit la différence d'expression entre les animaux N et IH.Nos résultats suggèrent que l'EI représente un traitement prometteur non pharmacologique ou complémentaire pour limiter les complications cardio-vasculaires induites par l’HI et le remodelage musculaire chez les patients atteints de SAOS. / Obstructive sleep apnea syndrome (OSAS) is a chronic disease characterized by repeated interruptions of breathing during sleep due to the temporary closure of the upper airway. Its prevalence increases with the increasing in prevalence of obesity, especially in developed countries.Chronic intermittent hypoxia (IH) resulting from this transient closure of the upper airway is one of the major consequences of OSAS and is responsible of most of the complications related to this pathology, including hypertension, myocardial infarction, atherosclerosis and more generally cardiovascular remodeling.On the other hand, intensive physical training(IT) is well known to have benefits on cardiovascular system, thus we hypothesize that physical training can reverse the deleterious effects of IH on reactivity and vascular remodeling as well as intracellular calcium signaling in muscle cells.To answer this question, we chose the rat as an animal model to study the potential effect of IT in the prevention and reversal of deleterious (IH) effects in terms of reactivity and calcium signaling in muscle tissue.Rats were exposed for 21 days to intermittent hypoxia and housed in cages specially equipped to maintain an airflow alternating between 21% and 5% PO2 in cages containing hypoxic rats and 21% PO2 in cages containing the control rats. During the last two weeks of exposure to IH, a group of hypoxic rats and one of the normoxic rats underwent IT sessions on a treadmill at a speed of 16m / min to 30m / min.Physiological parameters were measured (blood pressure, heart rate, hematocrit), the aorta was removed to study the vascular reactivity, then vascular smooth muscle cells were removed and cultured to study calcium signaling by EPIfluorescence microscopy. Finally, the genes coding for the key mediators of the calcium signaling: RyR1, RyR2 RyR3, (ryanodine receptors), TRPV4 (transient receptor potential channel), SERCA1, SERCA2 (Sarco / Endoplasmic Reticulum Ca2 + -ATPase) and IP3R1 , 5-Trisphosphate Receptor) in various vascular and skeletal tissues were studied at the molecular level as mRNA by Q-PCR or as protein by Western Blot.Our results show that IH induces a significant increase in blood pressure and hematocrit and a decrease in acetylcholine-induced aortic relaxation pre-contracted with phenylnephrine. This was consistent with our observation that HI increases the level of intracellular calcium in cultured aortic smooth muscle. On the other hand, IT induced a significant decrease in hematocrit and aortic vasoconstriction induced by phenylnephrine and endothelial-1, consistant with the observation that IT reduces the IH-N difference in the calcium response. On the molecular scale, IH induces a significant increase in the expression of RyR1, RyR2, RyR3, SERCA1, SERCA2, TRPV4 and IP3R1 at the mRNA level in the tissues of all groups with a greater amount of RyR1,RyR2,& RyR3 higher in IH tissue of smooth muscles (mainly in the thoracic and abdominal aorta) and SERCA1 (9-fold higher in IH tissues) and SERCA2 (10-fold higher in IH tissues) in the skeletal muscles (Gastrocnemius, plantaris and soléus). In addition, IH induces a significant increase in RYR1, RYR2 and TRPV4 at the protein level in the thoracic and abdominal aorta; And IT reduces the difference in expression between animals N and IH.Our results suggest that IT is a promising, non-pharmacological or complementary treatment for limiting cardiovascular complications induced by IH and muscle remodeling in patients with OSAS.