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Vascular Endothelial Growth Factor Receptor Blockade by SU5416 Combined With Pulsatile Shear Stress Causes Apoptosis and Subsequent Proliferation of Apoptosis-Resistant Endothelial Cells* FREE TO VIEW

Seiichiro Sakao, MD; Laimute Taraseviciene-Stewart; Jong Deog Lee, MD; Kathy Wood, RN; Carlyne D. Cool, MD; Norbert F. Voelkel, MD
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*From the Pulmonary Hypertension Center (Dr. Sakao, Mr. Taraseviciene-Stewart, Dr. Lee, and Dr. Voelkel) and Department of Pathology (Ms. Wood and Cool), University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Seiichiro Sakao, MD, University of Colorado Health Sciences Center, 4200 E Nonyj Ave, Denver, CO; e-mail: seiichiro.sakao@uchsc.edu

Chest. 2005;128(6_suppl):610S-611S. doi:10.1378/chest.128.6_suppl.610S-a
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Vascular endothelial growth factor (VEGF) is an obligatory survival factor for endothelial cells. We have demonstrated that the VEGF receptor blocker SU5416 in combination with long-term hypobaric hypoxia causes severe angioproliferative pulmonary hypertension (severe pulmonary hypertension) in rats, associated with precapillary arterial occlusion by proliferating endothelial cells. We believe that the development of severe angioproliferative pulmonary hypertension is associated with significant initial pulmonary endothelial cell death (apoptosis), and we postulate that the established, lumen-occluding lesions are the result of the subsequent emergence of apoptosis-resistant proliferating cells. In order to study the dependence of exuberant endothelial cell proliferation on initial apoptosis, we adapted the CELLMAX artificial capillary system to analyze the effects of SU5416 on human pulmonary microvascular endothelial cells under pulsatile shear stress. The immunohistochemical staining for Caspase-3 and proliferating cell nuclear antigen support our concept since SU5416 caused initial apoptosis (24 h after the SU5416 addition), whereas the surviving cells become hyperproliferative (proliferating cell nuclear antigen positive) and finally occlude the lumen. Flow cytometry for annexin V and BrdU showed that the apoptosis inhibitor prevent the proliferation following the initial apoptosis (Fig 1 ). These lumen-filling endothelial cells were apoptosis resistant. In conclusion, the endothelial cell death induced by the VEGF receptor blocker SU5416 and pulsatile shear stress may result in the selection of an apoptosis-resistant, proliferating endothelial cell phenotype.

Abbreviation: VEGF = vascular endothelial growth factor

Figure Jump LinkFigure 1. Flow cytometry for Annexin V and BrdU.Grahic Jump Location


Figure Jump LinkFigure 1. Flow cytometry for Annexin V and BrdU.Grahic Jump Location



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