Angiogenic factors and alveolar vasculature: development and alterations by injury in very premature baboons.
Proper formation of the pulmonary microvasculature is essential for normal lung development and gas exchange. Lung microvascular development may be disrupted by chronic injury of developing lungs in clinical diseases such as bronchopulmonary dysplasia. We examined microvascular development, angiogenic growth factors, and endothelial cell receptors in a fetal baboon model of chronic lung disease (CLD). In the last third of gestation, the endothelial cell marker platelet endothelial cell adhesion molecule (PECAM)-1 increased 7.5-fold, and capillaries immunostained for PECAM-1 changed from a central location in airspace septa to a subepithelial location. In premature animals delivered at 67% of term and supported with oxygen and ventilation for 14 days, PECAM-1 protein and capillary density did not increase, suggesting failure to expand the capillary network. The capillaries of the CLD animals were dysmorphic and not subepithelial. The angiogenic growth factor vascular endothelial growth factor (VEGF) and its receptor fms-like tyrosine kinase receptor (Flt-1) were significantly decreased in CLD. Angiopoietin-1, another angiogenic growth factor, and its receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domains were not significantly changed. These data suggest that CLD impairs lung microvascular development and that a possible mechanism is disruption of VEGF and Flt-1 expression.
Maniscalco
William M
WM
Division of Neonatology, Strong Children's Research Center, Department of Pediatrics, University of Rochester, 601 Elmwood Ave., Rochester, NY 14642, USA. William_Maniscalco@URMC.Rochester.edu
Watkins
Richard H
RH
Pryhuber
Gloria S
GS
Bhatt
Abhay
A
Shea
Colleen
C
Huyck
Heidie
H
D042683:Angiopoietin-1; D000818:Animals; D001997:Bronchopulmonary Dysplasia / Q000503:physiopathology*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000032:analysis / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007234:Infant, Premature; D008222:Lymphokines / Q000032:analysis / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics; D008833:Microcirculation / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010100:Oxygen / Q000494:pharmacology; D010215:Papio; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis / Q000235:genetics; D011650:Pulmonary Alveoli / Q000098:blood supply* / Q000737:chemistry / Q000254:growth & development; D011652:Pulmonary Circulation / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D042787:Receptor, TIE-2; D012121:Respiration, Artificial; D020545:Respiratory Mucosa / Q000098:blood supply / Q000737:chemistry / Q000254:growth & development; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D042683:Angiopoietin-1; D016228:Endothelial Growth Factors; D016326:Extracellular Matrix Proteins; D008222:Lymphokines; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C501162:FLT1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1; D010100:Oxygen