Angiopoietin-1 and VEGF in vascular development and angiogenesis in hypoplastic lungs.
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.
Chinoy
Mala R
MR
Lung Development Research Program, Department of Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. mchinoy@psu.edu
Graybill
Megan M
MM
Miller
Shane A
SA
Lang
C Max
CM
Kauffman
Gordon L
GL
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
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