title: Angiopoietin-1 and VEGF in vascular development and angiogenesis in hypoplastic lungs.
abstract: We hypothesized that exposure of murine fetuses to environmental toxins, such as nitrofen, during early embryogenesis alters vasculogenesis. To address our hypothesis, we assessed protein levels of endothelial cell-selective angiogenic factors: angiopoietin (ANG)-1, vascular endothelial growth factor (VEGF), and mediator of VEGF signaling, VEGF receptor-2 [fetal liver kinase (Flk)-1], a transmembrane receptor tyrosine kinase. VEGF and Flk-1 proteins were lower in hypoplastic lungs from pseudoglandular to alveolar stages than in normal lungs at equivalent developmental time points significant for induction of pulmonary vasculogenesis and angiogenesis. ANG-1 protein was higher in hypoplastic lungs than in normal lungs at all the developmental stages considered in this study, i.e., pseudoglandular, canalicular, saccular, and alveolar stages. We assessed exogenous VEGF-mediated endothelial cell response on extracellular signal-regulated kinase (ERK) 1/2, also referred to as p44/42 mitogen-activated protein kinase. Hypoplastic lungs had more elevated ERK 1/2 protein than normal developing lungs. Exposure to exogenous VEGF activated ERK 1/2 in normal developing lungs but not in hypoplastic lungs. Our results suggest that in hypoplastic lungs: 1) low VEGF signifies negative effects on vasculogenesis/angiogenesis and indicates altered endothelial-mesenchymal interactions; 2) increased ANG-1 protein may be required to maintain vessel integrity and quiescence; and 3) regulation of ERK 1/2 protein is affected in hypoplastic lungs. We speculate that extensive remodeling of blood vessels in hypoplastic lungs may occur to compensate for structurally and functionally defective vasculature.
authors.affiliation: Lung Development Research Program, Department of Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. mchinoy@psu.edu
authors.forename: Mala R
authors.initials: MR
authors.lastname: Chinoy
authors.forename: Megan M
authors.initials: MM
authors.lastname: Graybill
authors.forename: Shane A
authors.initials: SA
authors.lastname: Miller
authors.forename: C Max
authors.initials: CM
authors.lastname: Lang
authors.forename: Gordon L
authors.initials: GL
authors.lastname: Kauffman
mesh_terms: D042683:Angiopoietin-1; D000818:Animals; D002244:Carbon; D004396:Coloring Agents; D016228:Endothelial Growth Factors / Q000032:analysis / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000503:physiopathology*; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply* / Q000737:chemistry / Q000196:embryology; D008222:Lymphokines / Q000032:analysis / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008562:Membrane Glycoproteins / Q000032:analysis / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000503:physiopathology*; D010575:Pesticides / Q000633:toxicity; D010647:Phenyl Ethers / Q000633:toxicity; D011247:Pregnancy; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis; D017978:Receptors, Growth Factor / Q000032:analysis; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D004396:Coloring Agents; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D010575:Pesticides; D010647:Phenyl Ethers; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C028433:chinese ink; D002244:Carbon; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C007350:nitrofen