Central stiffening in adulthood linked to aberrant aortic remodeling under suboptimal intrauterine conditions

Abstract

This study examined perturbed aortic development and subsequent wall stiffening as a link to later cardiovascular disease. Placental insufficiency was induced in pregnant guinea pigs at midgestation by uterine artery ligation. Near term, fetuses were killed and defined as normal birth weight (NBW), low birth weight (LBW), and intrauterine growth restricted (IUGR). Offspring were classified according to birth weight and killed in adulthood. Collagen and elastin content of aortas were analyzed using Sirius red and orcein staining, respectively. Immunofluorescence was used for detection of ␣-actin and nonmuscle myosin heavy chain (MHC-B), a marker of synthetic-type vascular smooth muscle cells (VSMCs). Ex vivo generation of length-tension curves was performed with aortic rings from adult offspring. Relative elastic fiber content was decreased by 10% in LBW and 14% in IUGR compared with NBW fetuses. In adulthood, relative elastic fiber content was 51% lower in LBW vs. NBW, and the number of elastic laminae adjusted for wall thickness was 25% lower in LBW (P Ͻ 0.01). The percent area stained for MHC-B was sixfold higher in LBW vs. NBW fetuses (P Ͻ 0.0001) and threefold higher in LBW vs. NBW adult offspring (P Ͻ 0.05). The increase in MHC-B in LBW offspring concurred with a 41% increase in total collagen content and a 33 and 56% increase in relative and total ␣-actin content, respectively (P Ͻ 0.05). Thus aortic wall stiffening in adulthood can be traced to altered matrix composition established under suboptimal intrauterine conditions that is amplified postnatally by the activity of synthetic VSMCs.

Fetal Growth Restriction Induces Heterogeneous Effects on Vascular Biomechanical and Functional Properties in Guinea Pigs (Cavia porcellus)

“…Comparable effects of FGR on aorta remodeling have been reported in experimental models of FGR in sheep and guinea pigs (Thompson et al, 2011; Dodson et al, 2014). However, there is no clarity whether these structural alterations represent common changes in the entire circulatory system or are territory-specific.…”

“…A study on young adults shows that subjects born with FGR have a decreased internal diameter and increased stiffness in the ascending aorta (Bjarnegard et al, 2013). In this context, data from hypoxia-induced FGR in guinea pigs demonstrate the presence of vascular remodeling in the aorta of adult animals (Thompson et al, 2011). Similar changes in the in vivo structural and biomechanical properties of the aorta have been reported in children born with FGR (Bradley et al, 2010; Zanardo et al, 2011) suggesting that this altered vascular structure has an early onset.…”

Thoracic and abdominal aortas stiffen through unique extracellular matrix changes in intrauterine growth restricted fetal sheep

“…Hypoxia has been shown to be a strong modulator of structural vascular remodeling in fetal sheep thoracic aorta resulting in increased collagen content, transforming growth factor-␤ (TGF-␤ 1 ), matrix metalloproteinases, ␣-actin, and E-selectin and reduced elastin content (41). Remodeling in fetal aortic development due to IUGR stress in utero leads to structural remodeling resulting in aortic stiffening in the guinea pig as an adult (40). Therefore, both hemodynamics and oxygen tension appear to be important modulators of fetal vascular development and that development clearly has far-reaching implications beyond gestation.…”

Synaptic Development and Neuronal Myelination Are Altered with Growth Restriction in Fetal Guinea Pigs

“…All surgical and experimental procedures have been previously described [43] and were approved by The University of Western Ontario Animal Use Subcommittee and followed the guidelines of the Canadian Council on Animal Care. Chronic placental insufficiency was induced at midgestation (approx.…”