title: Anatomic closure of the premature patent ductus arteriosus: The role of CD14+/CD163+ mononuclear cells and VEGF in neointimal mound formation.
abstract: Permanent closure of the newborn ductus arteriosus requires the development of neointimal mounds to completely occlude its lumen. VEGF is required for neointimal mound formation. The size of the neointimal mounds (composed of proliferating endothelial and migrating smooth muscle cells) is directly related to the number of VLA4 mononuclear cells that adhere to the ductus lumen after birth. We hypothesized that VEGF plays a crucial role in attracting CD14/CD163 mononuclear cells (expressing VLA4) to the ductus lumen and that CD14/CD163 cell adhesion to the ductus lumen is important for neointimal growth. We used neutralizing antibodies against VEGF and VLA-4 to determine their respective roles in remodeling the ductus of premature newborn baboons. Anti-VEGF treatment blocked CD14/CD163 cell adhesion to the ductus lumen and prevented neointimal growth. Anti-VLA-4 treatment blocked CD14/CD163 cell adhesion to the ductus lumen, decreased the expression of PDGF-B (which promotes smooth muscle migration), and blocked smooth muscle influx into the neointimal subendothelial space (despite the presence of increased VEGF in the ductus wall). We conclude that VEGF is necessary for CD14/CD163 cell adhesion to the ductus lumen and that CD14/CD163 cell adhesion is essential for VEGF-induced expansion of the neointimal subendothelial zone.
authors.affiliation: Pharmaceutical Discovery Division, SRI International, Menlo Park, California 94025, USA.
authors.forename: Nahid
authors.initials: N
authors.lastname: Waleh
authors.forename: Steven
authors.initials: S
authors.lastname: Seidner
authors.forename: Donald
authors.initials: D
authors.lastname: McCurnin
authors.forename: Luis
authors.initials: L
authors.lastname: Giavedoni
authors.forename: Vida
authors.initials: V
authors.lastname: Hodara
authors.forename: Susan
authors.initials: S
authors.lastname: Goelz
authors.forename: Bao Mei
authors.initials: BM
authors.lastname: Liu
authors.forename: Christine
authors.initials: C
authors.lastname: Roman
authors.forename: Ronald I
authors.initials: RI
authors.lastname: Clyman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D004374:Ductus Arteriosus, Patent / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007231:Infant, Newborn; D039041:Integrin alpha4beta1 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D058426:Neointima; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010215:Papio; D011956:Receptors, Cell Surface / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000098902:CD163 Antigen
chemical_list: D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039041:Integrin alpha4beta1; D018950:Lipopolysaccharide Receptors; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III