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

The biologic processes of apoptosis and angiogenesis are linked in endothel ial biology because some endothelial cell growth factors also exert anti-ap optotic effects. We studied whether apoptosis is occurring in circulating e ndothelial cells (CEC) that have lost the survival signals derived from anc horage to extracellular matrix. Consistent with this expectation, 64% +/- 1 6% of CEC from normal donors showed evidence of apoptosis (by morphology an d 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 ap optotic. Vascular endothelial growth factor (VEGF) levels were significantl y (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 corre lation between VEGF and CEC apoptosis (r = .612, P = .001). Consistent with stimulation by VEGF, CEC from sickle donors exhibited increased expression of alpha(v)beta(3). In vitro experiments showed that VEGF inhibits apoptos is 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 matri x reattachment. These data suggest the hypothesis that sickle cell anemia i s a state of enhanced anti-apoptotic tone for endothelial cells. If true, t his has im plications for disease pathobiology, particularly the developmen t of neovascularizing retinopathy. (C) 1999 by The American Society of Hema tology.