Anatomic Closure of the Premature Patent Ductus Arteriosus: The Role of CD14+/CD163+ Mononuclear Cells and VEGF in Neointimal Mound Formation

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.

[1]  N. Hills,et al.  Relationship between circulating platelet counts and ductus arteriosus patency after indomethacin treatment. , 2011, The Journal of pediatrics.

[2]  A. Walch,et al.  Platelets contribute to postnatal occlusion of the ductus arteriosus , 2010, Nature Medicine.

[3]  J. Borén,et al.  Postnatal constriction, ATP depletion, and cell death in the mature and immature ductus arteriosus. , 2006, American journal of physiology. Regulatory, integrative and comparative physiology.

[4]  V. Hodara,et al.  Expression of CD154 by a Simian Immunodeficiency Virus Vector Induces Only Transitory Changes in Rhesus Macaques , 2005, Journal of Virology.

[5]  B. Yoder,et al.  The Role of Monocyte-Derived Cells and Inflammation in Baboon Ductus Arteriosus Remodeling , 2005, Pediatric Research.

[6]  P. Nathanielsz,et al.  Phenotypic changes associated with advancing gestation in maternal and fetal baboon lymphocytes. , 2004, Journal of reproductive immunology.

[7]  D. Ginzinger,et al.  Prostaglandin E2—Mediated Relaxation of the Ductus Arteriosus: Effects of Gestational Age on G Protein-Coupled Receptor Expression, Signaling, and Vasomotor Control , 2004, Circulation.

[8]  C. Roman,et al.  Effects of Hypoxia, Hypoglycemia, and Muscle Shortening on Cell Death in the Sheep Ductus Arteriosus , 2003, Pediatric Research.

[9]  P. Libby,et al.  Inflammation and Atherosclerosis , 2002, Circulation.

[10]  C. Koch,et al.  VEGF regulates remodeling during permanent anatomic closure of the ductus arteriosus. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[11]  C. Koch,et al.  Combined Prostaglandin and Nitric Oxide Inhibition Produces Anatomic Remodeling and Closure of the Ductus Arteriosus in the Premature Newborn Baboon , 2001, Pediatric Research.

[12]  G. Andelfinger,et al.  Characterization of PGE2 receptors in fetal and newborn lamb ductus arteriosus. , 2001, American journal of physiology. Heart and circulatory physiology.

[13]  YuqingHuo,et al.  Role of Vascular Cell Adhesion Molecule-1 and Fibronectin Connecting Segment-1 in Monocyte Rolling and Adhesion on Early Atherosclerotic Lesions , 2000 .

[14]  V. Koteliansky,et al.  Infusion of an antialpha4 integrin antibody is associated with less neoadventitial formation after balloon injury of porcine coronary arteries. , 2000, The Canadian journal of cardiology.

[15]  A. Beaudet,et al.  P-Selectin or Intercellular Adhesion Molecule (Icam)-1 Deficiency Substantially Protects against Atherosclerosis in Apolipoprotein E–Deficient Mice , 2000, The Journal of experimental medicine.

[16]  D. Bullard,et al.  Roles of leukocyte/endothelial cell adhesion molecules in the pathogenesis of vasculitis. , 1999, The American journal of medicine.

[17]  C. Koch,et al.  Permanent Anatomic Closure of the Ductus Arteriosus in Newborn Baboons: The Roles of Postnatal Constriction, Hypoxia, and Gestation , 1999, Pediatric Research.

[18]  T. Noda,et al.  Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Hynes,et al.  The combined role of P- and E-selectins in atherosclerosis. , 1998, The Journal of clinical investigation.

[20]  K. Hillan,et al.  Neutralizing anti‐vascular endothelial growth factor antibody completely inhibits angiogenesis and growth of human prostate carcinoma micro tumors in vivo , 1998, The Prostate.

[21]  U. Ikeda,et al.  Human monocyte-endothelial cell interaction induces platelet-derived growth factor expression. , 1998, Cardiovascular research.

[22]  A. Lumsden,et al.  Anti-VLA-4 antibody reduces intimal hyperplasia in the endarterectomized carotid artery in nonhuman primates. , 1997, Journal of vascular surgery.

[23]  E. Kunkel,et al.  Distinct phenotype of E-selectin-deficient mice. E-selectin is required for slow leukocyte rolling in vivo. , 1996, Circulation research.

[24]  R. Kramer,et al.  Changes in Endothelial Cell and Smooth Muscle Cell Integrin Expression during Closure of the Ductus Arteriosus: An Immunohistochemical Comparison of the Fetal, Preterm Newborn, and Full-Term Newborn Rhesus Monkey Ductus , 1996, Pediatric Research.

[25]  P. Kubes,et al.  The alpha 4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo , 1996, The Journal of experimental medicine.

[26]  A. Mantovani,et al.  Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. , 1996, Blood.

[27]  F. Lang,et al.  Mononuclear leukocytes invade rabbit arterial intima during thickening formation via CD18-and VLA-4-dependent mechanisms and stimulate smooth muscle migration. , 1995, Circulation research.

[28]  I. Zachary,et al.  Signalling mechanisms in the regulation of vascular cell migration. , 1995, Cardiovascular research.

[29]  T. Springer,et al.  The integrin VLA-4 supports tethering and rolling in flow on VCAM-1 , 1995, The Journal of cell biology.

[30]  B L Langille,et al.  Expression of ICAM-1 and VCAM-1 and monocyte adherence in arteries exposed to altered shear stress. , 1995, Arteriosclerosis, thrombosis, and vascular biology.

[31]  P. Kubes,et al.  Reductions in physiologic shear rates lead to CD11/CD18-dependent, selectin-independent leukocyte rolling in vivo. , 1994, Blood.

[32]  M. Davies,et al.  The expression of the adhesion molecules ICAM‐1, VCAM‐1, PECAM, and E‐selectin in human atherosclerosis , 1993, The Journal of pathology.

[33]  R. Ross,et al.  Role of endogenous platelet-derived growth factor in arterial smooth muscle cell migration after balloon catheter injury. , 1993, Arteriosclerosis and thrombosis : a journal of vascular biology.

[34]  Bing Li,et al.  Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo , 1993, Nature.

[35]  Timothy A. Springer,et al.  Adhesion receptors of the immune system , 1990, Nature.

[36]  D. Goeddel,et al.  Vascular endothelial growth factor is a secreted angiogenic mitogen. , 1989, Science.

[37]  D. Connolly,et al.  Vascular permeability factor, an endothelial cell mitogen related to PDGF. , 1989, Science.

[38]  Gary R. Grotendorst,et al.  Activated human monocytes express the c-sis proto-oncogene and release a mediator showing PDGF-like activity , 1986, Nature.