Insulin-Like Growth Factor-I Receptor-Mediated Vasculogenesis/Angiogenesis in Human Lung Development

• Published in: American journal of respiratory cell and molecular biology Vol. 28; no. 2; pp. 159 - 169
• Main Authors: Han, Robin N. N, Post, Martin, Tanswell, A. Keith, Lye, Stephen J
• Format: Journal Article
• Language: English
• Published: United States Am Thoracic Soc 01.02.2003; American Thoracic Society
• Subjects: Animals; Gene Expression Regulation, Developmental; Humans; Immunohistochemistry; In Situ Hybridization; In Vitro Techniques; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - metabolism; Lung - blood supply; Lung - embryology; Lung - metabolism; Neovascularization, Physiologic; Phosphorylation; Rats; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tyrosine - metabolism
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.4764

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.