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(Circulation Research. 2003;92:920.)
© 2003 American Heart Association, Inc.

Integrative Physiology

Increased Fibronectin Deposition in Embryonic Hearts of Retinol-Binding Protein–Null Mice

Christopher C. Wendler, Angela Schmoldt, George R. Flentke, Lauren C. Case, Loredana Quadro, William S. Blaner, John Lough, Susan M. Smith

From the Department of Cell Biology, Neurobiology, and Anatomy and the Cardiovascular Center (C.C.W., A.S., L.C.C., J.L.), Medical College of Wisconsin, Milwaukee; the Department of Nutritional Sciences (G.R.F., S.M.S.), University of Wisconsin-Madison; the Department of Medicine (W.S.B.), Columbia University College of Physicians and Surgeons, New York, NY; Institute of Cancer Research (L.Q.), Columbia University College of Physician and Surgeons, New York, NY; and the Department of Biological and Environmental Sciences (L.Q.), University of Sannio, Benevento, Italy.

Correspondence to Dr John W. Lough, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail jlough{at}mcw.edu

Precise regulation of retinoid levels is critical for normal heart development. Retinol-binding protein (RBP), an extracellular retinol transporter, is strongly secreted by cardiogenic endoderm. This study addresses whether RBP gene ablation affects heart development. Despite exhibiting an >85% decrease in serum retinol, adult RBP-null mice are viable, breed, and have normal vision when maintained on a vitamin A–sufficient diet. Comparison of RBP-null with wild-type (WT) hearts from embryos at day 9.0 (E9.0) through E12.5 revealed an RBP-null phenotype similar to that of other retinoid-deficient models. At an early stage, RBP-null hearts display retarded trabecular development, which recovers by E9.5. This is accompanied at E9.5 and E10.5 by precocious differentiation of subepicardial cardiac myocytes. Most remarkably, RBP-null hearts display augmented deposition of fibronectin protein in the cardiac jelly at E9.0 through E10.5 and in the outflow tract at E12.5. This phenomenon, which was detected by immunohistochemistry and Western blotting without increased fibronectin transcript levels, is accompanied by increased numbers of mesenchymal cells in the outflow tract but not in the atrioventricular canal. RBP-null cardiac myocytes, especially in the subepicardial layer, display increased cell proliferation. This phenotype may present a model of subclinical retinoid insufficiency characterized by alteration of an extracellular matrix component and altered cellular differentiation and proliferation, changes that may have functional consequences for adult cardiac function. This murine model may have relevance to fetal development in human populations with inadequate retinoid intake.

Key Words: retinol-binding protein knockout • retinoic acid • mouse heart development • cardiac jelly • fibronectin

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