© 2003 American Thoracic Society DOI: 10.1165/rcmb.4764 Insulin-Like Growth Factor-I Receptor–Mediated Vasculogenesis/Angiogenesis in Human Lung DevelopmentCIHR Group in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital; CIHR Group in Lung Development, Lung Biology Program, The Hospital for Sick Children; and Departments of Obstetrics and Gynaecology, Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada Address correspondence to: Robin N.N. Han, Rm. 870, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, 600 University Avenue, Toronto, Canada, M5G 1X5. E-mail: hanrobin{at}aol.com The structural and functional development of the pulmonary system is dependent upon appropriate early vascularization of the embryonic lung. Our previous in vitro studies in a rat model indicated that insulin-like growth factor-I (IGF-I) is a potent angiogenic agent for fetal lung endothelial cells. To assess its role on human vascular lung development, we first examined the expression of IGF-I/II and IGF receptor type I (IGF-IR) in human embryonic and fetal lung tissues at 4–12 wk of gestation. Immunohistochemical and in situ hybridization studies revealed the presence of IGF-I/II–IGF-IR ligands and mRNA transcripts in embryonic lungs as early as 4 wk gestation. Immunotargeting using an anti–IGF-IR neutralizing antibody on human fetal lung explants demonstrated a significant blockade of IGF-IR signaling. Inactivation of IGF-IR resulted in a loss of endothelial cells, accompanied by dramatic changes in fetal lung explant morphology. Terminal transferase dUTP end-labeling assay and TEM studies of anti–IGF-IR–treated lungs demonstrated numerous apoptotic mesenchymal cells. Rat embryonic lung explant studies further validated the importance of the IGF–IGF-IR system for lung vascular development. These data provide the first demonstration of IGF-I/II expression in the human lung in early gestation and indicate that the IGF family of growth factors, acting through the IGF-IR, is required as a survival factor during normal human lung vascularization.
Abbreviations: angiopoietin 1, Ang-1 • endothelial cell, EC • electron microscopy, EM • insulin-like growth factors I and II, IGF-I/II • insulin-like growth factor receptor type I, IGF-IR • phosphate-buffered saline, PBS • smooth muscle This article has been cited by other articles:
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