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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3824-3830
Sickle Cell Anemia as a Possible State of Enhanced Anti-Apoptotic
Tone: Survival Effect of Vascular Endothelial Growth
Factor on Circulating and Unanchored Endothelial Cells
Anna Solovey,
Lizhen Gui,
Sundaram Ramakrishnan,
Martin H. Steinberg, and
Robert P. Hebbel
From the Departments of Medicine and Pharmacology, University of
Minnesota, Minneapolis, MN; and the Department of Medicine, Veteran
Affairs Medical Center, Jackson, MS.
The biologic processes of apoptosis and angiogenesis are linked in
endothelial biology because some endothelial cell growth factors also
exert anti-apoptotic effects. We studied whether apoptosis is occurring
in circulating endothelial cells (CEC) that have lost the survival
signals derived from anchorage to extracellular matrix. Consistent with
this expectation, 64% ± 16% of CEC from normal donors showed
evidence of apoptosis (by morphology and TdT-mediated dUTP nick end
labeling [TUNEL] assay). However, only 30% ± 15% (P < .001 v normal) of CEC from donors with sickle cell anemia were apoptotic. Vascular endothelial growth factor (VEGF) levels were significantly (P = .001) higher in plasma of sickle donors (120.1 ± 81.4 pg/mL) than
that of normal donors (37.6 ± 34.6 pg/mL), and there was an inverse
correlation between VEGF and CEC apoptosis (r = .612, P = .001). Consistent with stimulation by VEGF, CEC from
sickle donors exhibited increased expression of
 v 3. In vitro experiments showed that VEGF
inhibits apoptosis for cultured endothelial cells that are kept
unanchored and not allowed to re-establish attachment to extracellular
matrix, thus demonstrating that VEGF provides survival signals
independent of its ability to promote matrix reattachment. These data
suggest the hypothesis that sickle cell anemia is a state of enhanced anti-apoptotic tone for endothelial cells. If true, this has
implications for disease pathobiology, particularly the development of
neovascularizing retinopathy.
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