Pathophysiological adaptations of resistance arteries in rat offspring exposed in utero to maternal obesity is associated with sex-specific epigenetic alterations.
Animals
Collagen
/ genetics
DNA Methylation
Diet, High-Fat
Endothelium, Vascular
/ physiopathology
Epigenesis, Genetic
Female
Male
Matrix Metalloproteinases
/ genetics
Obesity, Maternal
/ physiopathology
Potassium Channels
/ genetics
Pregnancy
Prenatal Exposure Delayed Effects
/ physiopathology
Rats
Rats, Sprague-Dawley
Sex Factors
Vascular Resistance
Journal
International journal of obesity (2005)
ISSN: 1476-5497
Titre abrégé: Int J Obes (Lond)
Pays: England
ID NLM: 101256108
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
23
04
2020
accepted:
27
01
2021
revised:
10
12
2020
pubmed:
28
2
2021
medline:
24
12
2021
entrez:
27
2
2021
Statut:
ppublish
Résumé
Maternal obesity impacts vascular functions linked to metabolic disorders in offspring, leading to cardiovascular diseases during adulthood. Even if the relation between prenatal conditioning of cardiovascular diseases by maternal obesity and vascular function begins to be documented, little is known about resistance arteries. They are of particular interest because of their specific role in the regulation of local blood flow. Then our study aims to determine if maternal obesity can directly program fetal vascular dysfunction of resistance arteries, independently of metabolic disorders. With a model of rats exposed in utero to mild maternal diet-induced obesity (OMO), we investigated third-order mesenteric arteries of 4-month old rats in absence of metabolic disorders. The methylation profile of these vessels was determined by reduced representation bisulfite sequencing (RRBS). Vascular structure and reactivity were investigated using histomorphometry analysis and wire-myography. The metabolic function was evaluated by insulin and glucose tolerance tests, plasma lipid profile, and adipose tissue analysis. At 4 months of age, small mesenteric arteries of OMO presented specific epigenetic modulations of matrix metalloproteinases (MMPs), collagens, and potassium channels genes in association with an outward remodeling and perturbations in the endothelium-dependent vasodilation pathways (greater contribution of EDHFs pathway in OMO males compared to control rats, and greater implication of PGI Our study reports a specific methylation profile of resistance arteries associated with vascular remodeling and vasodilation balance perturbations in offspring exposed in utero to maternal obesity, in absence of metabolic dysfunctions.
Sections du résumé
BACKGROUND/OBJECTIVES
Maternal obesity impacts vascular functions linked to metabolic disorders in offspring, leading to cardiovascular diseases during adulthood. Even if the relation between prenatal conditioning of cardiovascular diseases by maternal obesity and vascular function begins to be documented, little is known about resistance arteries. They are of particular interest because of their specific role in the regulation of local blood flow. Then our study aims to determine if maternal obesity can directly program fetal vascular dysfunction of resistance arteries, independently of metabolic disorders.
METHODS
With a model of rats exposed in utero to mild maternal diet-induced obesity (OMO), we investigated third-order mesenteric arteries of 4-month old rats in absence of metabolic disorders. The methylation profile of these vessels was determined by reduced representation bisulfite sequencing (RRBS). Vascular structure and reactivity were investigated using histomorphometry analysis and wire-myography. The metabolic function was evaluated by insulin and glucose tolerance tests, plasma lipid profile, and adipose tissue analysis.
RESULTS
At 4 months of age, small mesenteric arteries of OMO presented specific epigenetic modulations of matrix metalloproteinases (MMPs), collagens, and potassium channels genes in association with an outward remodeling and perturbations in the endothelium-dependent vasodilation pathways (greater contribution of EDHFs pathway in OMO males compared to control rats, and greater implication of PGI
CONCLUSIONS
Our study reports a specific methylation profile of resistance arteries associated with vascular remodeling and vasodilation balance perturbations in offspring exposed in utero to maternal obesity, in absence of metabolic dysfunctions.
Identifiants
pubmed: 33637953
doi: 10.1038/s41366-021-00777-7
pii: 10.1038/s41366-021-00777-7
doi:
Substances chimiques
Potassium Channels
0
Collagen
9007-34-5
Matrix Metalloproteinases
EC 3.4.24.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1074-1085Références
Padmanabhan V, Cardoso RC, Puttabyatappa M. Developmental programming, a pathway to disease. Endocrinology. 2016;157:1328–40.
Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ. 1989;298:564–7.
pubmed: 2495113
pmcid: 1835925
doi: 10.1136/bmj.298.6673.564
Persson PB, Persson AB. Foetal programming. Acta Physiol. 2019;227:e13403.
doi: 10.1111/apha.13403
Godfrey KM, Costello P, Lillycrop K. Development, epigenetics and metabolic programming. Nestle Nutr Inst Workshop Ser. 2016;85:71–80.
pubmed: 27088334
pmcid: 4880042
doi: 10.1159/000439488
Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–54.
pubmed: 12610534
doi: 10.1038/ng1089
Langley‐Evans SC. Nutrition in early life and the programming of adult disease: a review. J Hun Nutr Diet. 2015;28(s1):1–14.
Poston L, Caleyachetty R, Cnattingius S, Corvalán C, Uauy R, Herring S, et al. Preconceptional and maternal obesity: epidemiology and health consequences. Lancet Diabetes Endocrinol. 2016;4:1025–36.
pubmed: 27743975
doi: 10.1016/S2213-8587(16)30217-0
Mamun AA, O’Callaghan M, Callaway L, Williams G, Najman J, Lawlor DA. Associations of gestational weight gain with offspring body mass index and blood pressure at 21 years of age: evidence from a birth cohort study. Circulation. 2009;119:1720–7.
pubmed: 19307476
doi: 10.1161/CIRCULATIONAHA.108.813436
Reynolds RM, Allan KM, Raja EA, Bhattacharya S, McNeill G, Hannaford PC, et al. Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years. BMJ. 2013;347:f4539.
pubmed: 23943697
pmcid: 3805484
doi: 10.1136/bmj.f4539
Armitage JA, Lakasing L, Taylor PD, Balachandran AA, Jensen RI, Dekou V, et al. Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy. J Physiol. 2005;565:171–84.
pubmed: 15774514
pmcid: 1464506
doi: 10.1113/jphysiol.2005.084947
Khan IY, Dekou V, Douglas G, Jensen R, Hanson MA, Poston L, et al. A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring. Am J Physiol Regul Integr Comput Physiol. 2005;288:R127–133.
doi: 10.1152/ajpregu.00354.2004
Taylor P, Khan I, Hanson M, Poston L. Impaired EDHF-mediated vasodilatation in adult offspring of rats exposed to a fat-rich diet in pregnancy. J Physiol. 2004;558(Pt 3):943–51.
pubmed: 15194731
pmcid: 1665032
doi: 10.1113/jphysiol.2002.018879
Frias AE, Grove KL. Obesity: a transgenerational problem linked to nutrition during pregnancy. Semin Reprod Med. 2012;30:472–8.
pubmed: 23074005
pmcid: 3615704
doi: 10.1055/s-0032-1328875
Agarwal P, Morriseau TS, Kereliuk SM, Doucette CA, Wicklow BA, Dolinsky VW. Maternal obesity, diabetes during pregnancy and epigenetic mechanisms that influence the developmental origins of cardiometabolic disease in the offspring. Crit Rev Clin Lab Sci. 2018;55:71–101.
pubmed: 29308692
doi: 10.1080/10408363.2017.1422109
Krause B, Sobrevia L, Casanello P. Epigenetics: new concepts of old phenomena in vascular physiology. Curr Vasc Pharmacol. 2009;7:513–20.
pubmed: 19485890
doi: 10.2174/157016109789043883
Ilaria Floris, Betty Descamps, Antonella Vardeu, Tijana Mitić, Maria PosadinoAnna, Saran Shantikumar, et al. Gestational diabetes mellitus impairs fetal endothelial cell functions through a mechanism involving microRNA-101 and histone methyltransferase enhancer of zester homolog-2. Arterioscler Thromb Vasc Biol. 2015;35:664–74.
doi: 10.1161/ATVBAHA.114.304730
Mulvany MJ. Structure and function of small arteries in hypertension. J Hypertens Suppl. 1990;8:S225–32.
pubmed: 2095391
Félétou M, Huang Y, Vanhoutte PM. Vasoconstrictor prostanoids. Pflugers Arch. 2010;459:941–50.
pubmed: 20333529
doi: 10.1007/s00424-010-0812-6
Musa MG, Torrens C, Clough GF. The microvasculature: a target for nutritional programming and later risk of cardio-metabolic disease. Acta Physiol. 2014;210:31–45.
doi: 10.1111/apha.12131
Loufrani L, Henrion D. Role of the cytoskeleton in flow (shearstress)-induced dilation and remodeling in resistance arteries. Med Biol Eng Comput. 2008;46:451–60.
pubmed: 18246377
pmcid: 2566739
doi: 10.1007/s11517-008-0306-2
Brayden JE, Li Y, Tavares MJ. Purinergic receptors regulate myogenic tone in cerebral parenchymal arterioles. J Cereb Blood Flow Metab. 2013;33:293–9.
pubmed: 23168530
doi: 10.1038/jcbfm.2012.169
Xu J, Mathur J, Vessières E, Hammack S, Nonomura K, Favre J, et al. GPR68 senses flow and is essential for vascular physiology. Cell. 2018;173:762–775.e16.
pubmed: 29677517
pmcid: 5951615
doi: 10.1016/j.cell.2018.03.076
Zicha J, Kuneš J. Ontogenetic aspects of hypertension development: analysis in the rat. Physiol Rev. 1999;79:1227–82.
pubmed: 10508234
doi: 10.1152/physrev.1999.79.4.1227
Krueger F, Andrews SR. Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics. 2011;27:1571–2.
pubmed: 21493656
pmcid: 3102221
doi: 10.1093/bioinformatics/btr167
Wreczycka K, Gosdschan A, Yusuf D, Grüning B, Assenov Y, Akalin A. Strategies for analyzing bisulfite sequencing data. J Biotechnol. 2017;261:105–15.
pubmed: 28822795
doi: 10.1016/j.jbiotec.2017.08.007
Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinform. 2009;10:48.
doi: 10.1186/1471-2105-10-48
Mulvany MJ, Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res. 1977;41:19–26.
pubmed: 862138
doi: 10.1161/01.RES.41.1.19
Christensen KL, Mulvany MJ. Mesenteric arcade arteries contribute substantially to vascular resistance in conscious rats. J Vasc Res. 1993;30:73–79.
pubmed: 8504198
doi: 10.1159/000158978
Sengupta P. The laboratory rat: relating its age with human’s. Int J Prev Med. 2013;4:624–30.
pubmed: 23930179
pmcid: 3733029
Sofronova SI, Borzykh AA, Gaynullina DK, Kuzmin IV, Shvetsova AA, Lukoshkova EV. et al. Endothelial nitric oxide weakens arterial contractile responses and reduces blood pressure during early postnatal development in rats. Nitric Oxide. 2016;55–56:1–9.
pubmed: 26923819
doi: 10.1016/j.niox.2016.02.005
Alarcon G, Roco J, Medina M, Medina A, Peral M, Jerez S. High fat diet-induced metabolically obese and normal weight rabbit model shows early vascular dysfunction: mechanisms involved. Int J Obes. 2018;42:1535–43.
doi: 10.1038/s41366-018-0020-6
Begg LM, Palma-Dias R, Wang J, Chin-Dusting JPF, Skilton MR. Maternal adiposity and newborn vascular health. Archives of Disease in Childhood. 2013;98:F279–F280.
pubmed: 23447583
doi: 10.1136/archdischild-2012-303566
Sundholm JKM, Litwin L, Rönö K, Koivusalo SB, Eriksson JG, Sarkola T. Maternal obesity and gestational diabetes: impact on arterial wall layer thickness and stiffness in early childhood—RADIEL study six-year follow-up. Atherosclerosis. 2019;284:237–44.
pubmed: 30819513
doi: 10.1016/j.atherosclerosis.2019.01.037
Hopps E, Caimi G. Matrix metalloproteinases in metabolic syndrome. Eur J Intern Med. 2012;23:99–104.
pubmed: 22284236
doi: 10.1016/j.ejim.2011.09.012
Gonzalez RJ, Lin S-A, Bednar B, Connolly B, LaFranco-Scheuch L, Mesfin GM, et al. Vascular imaging of matrix metalloproteinase activity as an informative preclinical biomarker of drug-induced vascular injury. Toxicol Pathol. 2017;45:633–48.
Dumont O, Loufrani L, Henrion D. Key role of the NO-pathway and matrix metalloprotease-9 in high blood flow-induced remodeling of rat resistance arteries. Arterioscler Thromb Vasc Biol. 2007;27:317–24.
pubmed: 17158349
doi: 10.1161/01.ATV.0000254684.80662.44
Huang Y, Zhao J-X, Yan X, Zhu M-J, Long NM, McCormick RJ, et al. Maternal obesity enhances collagen accumulation and cross-linking in skeletal muscle of ovine offspring. PLoS ONE. 2012;7:e31691.
pubmed: 22348119
pmcid: 3279401
doi: 10.1371/journal.pone.0031691
Huang Y, Yan X, Zhao JX, Zhu MJ, McCormick RJ, Ford SP, et al. Maternal obesity induces fibrosis in fetal myocardium of sheep. Am J Physiol Endocrinol Metab. 2010;299:E968–975.
pubmed: 20876759
pmcid: 3006252
doi: 10.1152/ajpendo.00434.2010
Hawkes CA, Gentleman SM, Nicoll JA, Carare RO. Prenatal high-fat diet alters the cerebrovasculature and clearance of β-amyloid in adult offspring. J. Pathol. 2015;235:619–31.
pubmed: 25345857
doi: 10.1002/path.4468
Hashimoto K, Kugo H, Tanaka H, Iwamoto K, Miyamoto C, Urano T, et al. The effect of a high-fat diet on the development of abdominal aortic aneurysm in a vascular hypoperfusion-induced animal model. JVR. 2018;55:63–74.
Phang M, Ross J, Raythatha JH, Dissanayake HU, McMullan RL, Kong Y, et al. Epigenetic aging in newborns: role of maternal diet. Am J Clin Nutr. 2020;111:555–61.
pubmed: 31942922
doi: 10.1093/ajcn/nqz326
Ribaroff GA, Wastnedge E, Drake AJ, Sharpe RM, Chambers TJG. Animal models of maternal high fat diet exposure and effects on metabolism in offspring: a meta-regression analysis. Obes Rev. 2017;18:673–86.
pubmed: 28371083
pmcid: 5434919
doi: 10.1111/obr.12524
Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AHK. is an endothelium-derived hyperpolarizing factor in rat arteries. Nature. 1998;396:269–72.
pubmed: 9834033
doi: 10.1038/24388
Shaul PW, Kinane B, Farrar MA, Buja LM, Magness RR. Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery. Alterations after prolonged hypoxia in the rat. J Clin Investig. 1991;88:447–55.
pubmed: 1864958
pmcid: 295357
doi: 10.1172/JCI115324
Gray C, Vickers MH, Segovia SA, Zhang XD, Reynolds CM. A maternal high fat diet programmes endothelial function and cardiovascular status in adult male offspring independent of body weight, which is reversed by maternal conjugated linoleic acid (CLA) supplementation. PLoS ONE. 2015;10:e0115994.
pubmed: 25695432
pmcid: 4335063
doi: 10.1371/journal.pone.0115994
Carnevale D, Facchinello N, Iodice D, Bizzotto D, Perrotta M, De Stefani D, et al. Loss of EMILIN-1 enhances arteriolar myogenic tone through TGF-β (transforming growth factor-β)-dependent transactivation of EGFR (epidermal growth factor receptor) and is relevant for hypertension in mice and humans. Arterioscler Thromb Vasc Biol. 2018;38:2484–97.
pubmed: 30354220
doi: 10.1161/ATVBAHA.118.311115
Freed JK, Gutterman DD. Communication is key: mechanisms of intercellular signaling in vasodilation. J Cardiovasc Pharmacol. 2017;69:264–72.
pubmed: 28482351
pmcid: 5424612
doi: 10.1097/FJC.0000000000000463
Garland CJ, Dora KA. EDH: endothelium-dependent hyperpolarization and microvascular signalling. Acta Physiol. 2017;219:152–61.
doi: 10.1111/apha.12649