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Vascular Endothelial Growth Factor Regulates Clearance of Apoptotic Cells

Implications for Emphysema

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado; and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to R. William Vandivier, M.D., University of Colorado at Denver Health Sciences Center, 4200 E. Ninth Ave., Box C272, Denver, CO 80262. E-mail: Bill.Vandivier{at}uchsc.edu

Apoptosis and the removal of apoptotic cells (efferocytosis) are tightly coupled with the regulation of normal lung structure. Processes that disrupt, or uncouple, this balance have the potential to alter normal cell turnover, ultimately resulting in the induction of lung pathology and disease. Human emphysema is associated with increased apoptosis and decreased vascular endothelial growth factor (VEGF), a key angiogenic growth factor. Direct involvement of VEGF and its receptors in the induction of emphysema was further suggested when SU5416, an inhibitor of the VEGF receptor (R) 1 and 2, rapidly induced emphysema in rats and increased lung apoptotic cells. We sought to test the effect of VEGF and its receptors on efferocytosis. Initial experiments demonstrated that SU5416 inhibited efferocytosis by human monocyte–derived macrophages in a dose-dependent manner, but had no effect on ingestion of latex beads or IgG-opsonized erythrocytes. As macrophages synthesize VEGF, which may act in an autocrine fashion to stimulate VEGF-R1, neutralizing antibodies against VEGF and VEGF-R1 were tested; both inhibited efferocytosis. The VEGF-R1–neutralizing antibody also inhibited uptake through the phosphatidylserine receptor, an important efferocytosis receptor. In vivo, SU5416 inhibited clearance of apoptotic thymocytes after intratracheal administration in mice. Therefore, VEGF may perform a dual role in the lung by regulating both apoptosis and efferocytosis, such that disruption of VEGF signaling may dysregulate lung homeostasis and contribute to the pathogenesis of emphysema.

FOOTNOTES

This study was funded by KO-8 HL072018.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form March 20, 2006; accepted in final form March 28, 2006)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Vandivier, R. W. Articles by Henson, P. M. Search for Related Content PubMed Articles by Vandivier, R. W. Articles by Henson, P. M.