Nutrient Restriction In Utero Induces Remodeling of the Vascular Extracellular Matrix in Rat Offspring

Abstract

The uterine environment may influence the development of chronic diseases later in life. The authors hypothesized that maternal nutritional restriction prenatally induces remodeling of offspring blood vessels such that they become stiff and contribute to the development of adult hypertension. To test this hypothesis, the authors studied the blood vessels of offspring of dams that were exposed to 50% maternal food restriction (MFR) from e10 to term as compared to age-matched controls. In aortas of MFR offspring, there was a significant increase in elastin and glycosaminoglycans (GAG) at 1 day of age. By 2 months of life, there was a significant increase in collagen and a decrease in GAG in MFR offspring aortas. A redistribution of elastin was also noted in MFR offspring, with a significant decrease in the interelastin laminae at both 1 day and 2 months. In mesenteric arterioles of MFR offspring, there was a decrease in GAG in 1-day-old and 2-month-old MFR offspring. There were no changes in elastin in both age groups in mesenteric arterioles, and by 2 months of life, collagen deposition was also found in these resistance vessels. There was a significant increase in expression of matrix metalloproteinase 9 (MMP-9) mRNA in 1-day-old MFR aortas, while both MMP-9 and MMP-2 expression was increased in the 4-month-old MFR aortas. These results indicate a significant remodeling of the extracellular matrix occurs in both conduit and resistance vessels. By 2 months of life, the compositions of both vessel types are consistent with stiff vessels, a contributing factor to hypertension.

Keywords

Extracellular matrix collagen elastin glycosaminoglycans aorta mesenteric arterioles maternal food restriction

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References

Barker DJ , Osmond C . Death rates from stroke in England and Wales predicted from past maternal mortality. Br Med J (Clin Res Ed). 1987;295:83-86.

Gennser G , Rymark P , Isberg PE . Low birth weight and risk of high blood pressure in adulthood. Br Med J (Clin Res Ed). 1988;296:1498-1500.

McMillen IC , Robinson JS . Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev. 2005;85:571-633.

Pladys P , Sennlaub F , Brault S , et al. Microvascular rarefaction and decreased angiogenesis in rats with fetal programming of hypertension associated with exposure to a low protein diet in utero. Am J Physiol Regul Integr Comp Physiol. 2005;289: R1580-R1588.

Armitage JA , Lakasing L , Taylor PD , et al. Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy. J Physiol. 2005;565: 171-184.

Brawley L , Poston L , Hanson MA . Mechanisms underlying the programming of small artery dysfunction: review of the model using low protein diet in pregnancy in the rat. Arch Physiol Biochem. 2003;111:23-35.

Shadwick RE . Mechanical design in arteries. J Exp Biol.1999;202:3305-3313.

Dobrin PB . Mechanical properties of arteries. Physiol Rev.1978;58:397-460.

Behmoaras J , Osborne-Pellegrin M , Gauguier D , Jacob MP . Characteristics of the aortic elastic network and related phenotypes in seven inbred rat strains. Am J Physiol Heart Circ Physiol. 2005;288:H769-H777.

10.

Kreese H , Schonherr E . Proteoglycan of the extracellular matrix and growth control. J Cell Physiol. 2001;189:266-274.

11.

Foster JA , Rich CB , Miller M , Benedict MR , Richman RA , Florini JR . Effect of age and IGF-I administration on elastin gene expression in rat aorta. J Gerontol. 1990;45:B113-B118.

12.

Kahari VM , Olsen DR , Rhudy RW , Carrillo P , Chen YQ , Uitto J .Transforming growth factor-beta up-regulates elastin gene expression in human skin fibroblasts. Evidence for posttranscriptional modulation. Lab Invest. 1992;66:580-588.

13.

Desai M , Gayle D , Babu J , Ross MG . Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol. 2005;288:R91-R96.

14.

Momeni M , Han G , Ross MG , Desai M , Khorram O . Maternal food restricts (FR) induces remodeling of the vascular extracellular matrix in the offspring. J Soc Gyn Invest. 2006;13(suppl):185A-185A.

15.

Kielty CM , Sherratt MJ , Marson A , Baldock C . Fibrillin microfibrils. Adv Protein Chem. 2005;70:405-436.

16.

Karnik SK , Brooke BS , Bayes-Genis A , et al.A critical role for elastin signaling in vascular morphogenesis and disease. Development. 2003;130:411-423.

17.

Sadoun E , Reed MJ . Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response,and growth factor expression. J Histochem Cytochem. 2003;51:1119-1130.

18.

Laurent S , Boutouyrie P , Lacolley P . Structural and genetic bases of arterial stiffness. Hypertension. 2005;45:1050-1055.

19.

Briones AM , Gonzales JM , Somoza B , et al. Role of elastin in spontaneously hypertensive rat small mesenteric artery remodeling. J Physiol. 2003;552:185-189.

20.

Wight TN . Cell biology of arterial proteoglycans. Arteriosclerosis. 1989;9:1-20.

21.

Gandley RE , McLaughlin MK , Koob TJ , Little SA , McGuffee LJ . Contribution of chondroitin-dermatan sulfate-containing proteoglycans to the function of rat mesenteric arteries. Am J Physiol. 1997;273:H952-H960.

22.

Et-Taouil K , Schiavi P , Levy BI , Plante GE . Sodium intake, large artery stiffness, and proteoglycans in the spontaneously hypertensive rat. Hypertension. 2001;38:1172-1176.

23.

Martin H , Hu J , Gennser G , Norman M . Impaired endothelial function and increased carotid stiffness in 9-year old children with low birth-weight. Circulation. 2000;102:2739-2744.

24.

Riedel M , Rafflenbeul W , Lichten P . Ovarian sex steroids and atheroscerosis. Clin Investig. 1993;71:406-412.

25.

Vassilev V , Pretto CM , Coronet PB , et al. Response of matrix metalloproteinases and tissue inhibitors of metalloproteinases messenger ribonucleic acids to ovarian steroids in human endometrial explants mimics their gene and phase-specific differential control in vivo. J Clin Endocrinol Metab. 2005;90: 5848-5857.

26.

Jacob MP . Extracellular matrix remodeling and matrix metalloproteinases in the vascular wall during aging and in pathological conditions. Biomed Pharmacother. 2003;57:195-202.

27.

Van der RM , Garrone R . Collagen family of proteins. FASEB J. 1991;5:2814-2823.

28.

Yasmin, Wallace S , McEniery CM , et al. Matrix metalloproteinase-9 (MMP-9), MMP-2 and serum elastase activity are associated with systolic hypertension and arterial stiffness. Artioscler Thromb Vasc Biol. 2005;25:372-378.

29.

Blankenberg S , Rupprecht HJ , Poirier O , et al. Plasma concentrations and genetic variation of matrix metalloproteinase 9 and prognosis of patients with cardiovascular disease. Circulation. 2003;107:1579-1585.

30.

Borden P , Heller RA .Transcriptional control of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Crit Rev Eukaryot Gene Expr. 1997;7:159-178.

31.

Kossakowska AE , Edwards DR , Prusinkiewicz C , et al. Interleukin-6 regulation of matrix metalloproteinase (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase (TIMP- 1) expression in non-Hodgkin's lymphomas. Blood. 1999;94: 2020-2029.

32.

Takeshita S , Tokutomi T , Kawase H , et al. Elevated serum levels of matrix metalloproteinase-9 (MMP-9) in Kawasaki disease. Clin Exp Immunol. 2001;125:340-344.

33.

Nkkari ST , Hoyhtya M , Isola J , Nikkari T . Macrophages contain 92-kd gelatinase (MMP-9) at the site of degenerated internal elastic lamina in temporal arteritis. Am J Pathol.1996;149:1427-1433.

34.

Intengan HD , Schiffrin EL .Vascular remodeling in hypertension: roles of apoptosis, inflammation and fibrosis. Hypertension. 2001;38:581-587.

35.

Lee T , Esemuede N , Sumpio BE , Gahtan V . Thrombospond in-1 induces matrix metalloproteinase-2 activation in vascular smooth muscle cells. J Vasc Surg. 2003;38:147-154.

36.

Touyz RM . Intracellular mechanisms involved in vascular remodeling of resistance arteries in hypertension:role of angiotensin ll. Exp Physiol. 2005;90:449-455.

37.

Mey JGR , Schiffers PM , Hilgers RHP , Sanders MM .Toward functional genomics of flow-induced outward remodeling of resistance arteries. Am J Physiol Heart Circ Physiol. 2005;288: H1022-H1027.