Cyclic angiogenesis and blood vessel regression in the ovary: blood vessel regression during luteolysis involves endothelial cell detachment and vessel occlusion.

Angiogenesis occurs as a cyclically regulated process in the ovary and the uterus. After ovulation, there is massive sprouting of blood vessels in the growing corpus luteum (CL) during the first third of the ovarian cycle. During luteolysis and for several weeks thereafter, all newly formed vessels regress. Here we have systematically analyzed regression of blood vessels during luteolysis to identify mechanisms of blood vessel regression. Blood vessel counts are highest in the midcycle CL and drop rapidly after the onset of luteolysis. After a rapid phase of tissue dissociation, blood vessel regression proceeds slowly over several weeks in the residual CL. Endothelial cells in regressing vessels acquire a distinctly rounded and condensed phenotype. Ultrastructural analysis of blood vessel regression processes in the cyclic CL suggests two major mechanisms of blood vessel regression: a) detachment of rounded endothelial cells from their basement membrane, leaving areas devoid of covering endothelial cell monolayer, and b) contraction and occlusion of arterioles and small arteries with pronounced proliferation of smooth muscle cells. In situ detection of nucleosomal fragmentation products demonstrates numerous apoptotic luteal cells, but only a few apoptotic endothelial cells in the regressing CL. Induction of apoptosis in cultured endothelial cell monolayers by RGD peptides demonstrated that endothelial cells detach from their adhesive surface before fully becoming positive for nucleosomal fragmentation products. These data indicate that cyclic angiogenic processes in the ovary offer a suitable experimental system to analyze mechanisms of blood vessel growth and regression, and suggest that detachment of endothelial cells before apoptosis as well as contractive occlusion of blood vessels may be critical determinants of blood vessel regression.