Submitted on January 11, 2006
Accepted on July 5, 2007
Maternal vitamin A alters gene profiles and structural maturation of the rat ductus arteriosus
Utako Yokoyama1, Yoji Sato2, Toru Akaike3, Seiichi Ishida4, Junichi Sawada5, Taku Nagao2, Hong Quan3, Meihua Jin3, Mari Iwamoto6, Shumpei Yokota6, Yoshihiro Ishikawa7, and Susumu Minamisawa8*
1 Department of Physiology, Yokohama City University, Yokohama, Kanagawa, Japan
2 Division of Cellular and Gene Therapy Products, National Institute of Health Sciences, Tokyo, Japan
3 Department of Physiology, Yokohama City University, Japan
4 Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan
5 Division of Biochemistry and Immunochemistry, National Institute of Health Sciences, Tokyo, Japan
6 Department of Pediatrics, Yokohama City University, Yokohama, Kanagawa, Japan
7 Department of Physiology, Yokohama City University, Yokohama, Kanagawa, Japan; Department of Cell Biology and Molecular Medicine and Medicine (Cardiology), New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, United States
8 Department of Physiology, Yokohama City University, Yokohama, Kanagawa, Japan; Life Science and Medical Bio-Science, Waseda University, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: sminamis{at}yokohama-cu.ac.jp.
Retinoic acid (RA), a metabolite of vitamin A, has been proposed to regulate vascular remodeling and reactivity of the ductus arteriosus (DA). Using rat Affymetrix GeneChips, we found that a considerable number of genes in DA varied their expression levels in accordance with developmental mode: namely, preterm-, term-, and postnatal dominant clusters. Among a total of 8740 probe sets, maternal vitamin A administration (MVA) changed the expression levels of 91 genes (116 probe sets) more than 2.5-fold. About half of preterm- and term-dominant genes responded to MVA, whereas only 5% of postnatal dominant genes responded to MVA, indicating that fetal dominant genes were susceptible to RA signals. The expression levels of 51 genes in MVA-treated DA at preterm were similar to the expression levels in non-treated DA at term, indicating that the global gene profile at preterm resembled that of the control animal at term. We observed neointima formation in MVA-treated DA at preterm in accordance with upregulation of fibronectin and hyaluronic acid, whereas it was rarely observed in non-treated DA at preterm. Five fetal cardiac myofibrillar genes were also upregulated in MVA-treated in vivo DA, whereas they were developmentally downregulated in non-treated DA. The present study indicates that MVA-mediated alteration in gene profile was associated with early structural maturation of DA, although MVA-mediated maturation may differ from normal vascular remodeling of DA.
