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.
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Abbreviations
- COX:
-
cyclooxygenase
- ΔCT:
-
the difference in cycle threshold between the expression of the housekeeping gene MDH and the gene of interest
- eNOS:
-
endothelial NOS
- HP1/2:
-
monoclonal antibody against VLA-4
- MDH:
-
malate dehydrogenase
- MMP-9:
-
matrix metalloproteinase-9
- VCAM-1:
-
vascular cell adhesion molecule-1
- VE:
-
vascular endothelial cell
- VLA-4 or CD49d:
-
α4β1 integrin mononuclear cell adhesion receptor
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Acknowledgements
We thank Dr. Napoleone Ferrara (Genentech) for providing us with MAb A.4.6.1. We also thank Ms. Vickie Winter, Dr. Jackie Coalson, and all the personnel at the BPD Resource Center and the University of Texas Health Science Center at San Antonio, Pathology Division.
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Supported by grants from U.S. Public Health Service [NIH grants HL46691, HL56061, HL52636 BPD Resource Center, and P51RR13986 (NCRR)] and by a gift from the Jamie and Bobby Gates Foundation. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant number C06 RR12087 (NCRR).
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Waleh, N., Seidner, S., McCurnin, D. et al. Anatomic Closure of the Premature Patent Ductus Arteriosus: The Role of CD14+/CD163+ Mononuclear Cells and VEGF in Neointimal Mound Formation. Pediatr Res 70, 332–338 (2011). https://doi.org/10.1203/PDR.0b013e3182294471
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DOI: https://doi.org/10.1203/PDR.0b013e3182294471
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