title: Intrauterine growth restriction influences vascular remodeling and stiffening in the weanling rat more than sex or diet.
abstract: Intrauterine growth restriction (IUGR) increases the incidence of adult cardiovascular disease (CVD). The sex-specific developmental mechanisms for IUGR-induced and Western high-fat diet (HFD) modification of CVD remain poorly understood. We hypothesized a maternal HFD in the Sprague-Dawley rat would augment IUGR-induced CVD in the offspring through decreased cardiac function and increased extracellular matrix (ECM) remodeling and stiffness in a sex-specific manner. HFD or regular diet (Reg) was given from 5 wk before mating through postnatal day (PND) 21. IUGR was induced by uterine artery ligation at embryonic day 19.5 (term = 21.5 days). At PND 21, echocardiographic assessments were made and carotid arteries tested for vascular compliance using pressure myography. Arterial samples were quantified for ECM constituents or fixed for histologic evaluation. The insult of IUGR (IUGR + Reg and IUGR + HFD) led to increased mechanical stiffness in both sexes (P < 0.05). The combination of IUGR + HFD increased diastolic blood pressure 47% in males (M) and 35% in females (F) compared with the Con + Reg (P < 0.05). ECM remodeling in IUGR + HFD caused fewer (M = -29%, F = -24%) but thicker elastin bands (M = 18%, F = 18%) and increased total collagen (M = 49%, F = 34%) compared with Con + Reg arteries. Remodeling in IUGR + HFD males increased medial collagen and soluble collagen (P < 0.05). Remodeling in IUGR + HFD females increased adventitial collagen and wall thickness (P < 0.05) and decreased matrix metalloproteinase 2 (MMP-2), advanced glycosylation end products (AGE), and receptor AGE (RAGE; P < 0.05). In summary, both IUGR + Reg and IUGR + HFD remodel ECM in PND 21 rats. While IUGR + HFD increases blood pressure, IUGR but not HFD increases vascular stiffness suggesting a specific mechanism of vascular remodeling that can be targeted to limit future disease.
  We report intrauterine growth restriction (IUGR) increases vascular stiffening in both male and female rats through increased collagen content and altered elastin structure more than a high-fat diet (HFD) alone. Our study shows the importance of stiffness supporting the hypothesis that there are physiologic differences and potential windows for early intervention targeting vascular remodeling mechanisms.
authors.affiliation: Department of Surgery, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado.|Department of Bioengineering, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado.|The Pediatric Heart Lung Center, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado.|The Laboratory for Fetal and Regenerative Biology, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado.
authors.forename: R Blair
authors.initials: RB
authors.lastname: Dodson
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, University of Utah, Salt Lake City, Utah; and.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
authors.affiliation: Department of Surgery, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado.|The Pediatric Heart Lung Center, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado.|The Laboratory for Fetal and Regenerative Biology, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Kyle
authors.initials: K
authors.lastname: Powers
authors.affiliation: Division of Pediatric Cardiology, Department of Pediatrics, University of Utah, Salt Lake City, Utah; and.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Baifeng
authors.initials: B
authors.lastname: Yu
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah.
authors.forename: Kurt H
authors.initials: KH
authors.lastname: Albertine
authors.affiliation: Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, Utah erin.zinkhan@hsc.utah.edu.
authors.forename: Erin K
authors.identifier: http://orcid.org/0000-0001-6085-6976
authors.initials: EK
authors.lastname: Zinkhan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000502:physiology*; D002339:Carotid Arteries / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism; D059305:Diet, High-Fat; D004452:Echocardiography; D004549:Elastin / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006321:Heart / Q000503:physiopathology; D008026:Ligation; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012737:Sex Factors; D055988:Uterine Artery / Q000601:surgery; D066253:Vascular Remodeling / Q000502:physiology*; D059289:Vascular Stiffness / Q000502:physiology*; D014886:Weaning
chemical_list: D003094:Collagen; D004549:Elastin
keywords: collagen; elastin; extracellular matrix; high-fat diet