The development, function and regression of the primate corpus luteum during the luteal phase of the menstrual cycle is accompanied by, and presumably dependent upon, formation, maintenance and degeneration of the luteal microvasculature. Recent studies established that microvascular endothelial cells comprise >95% of proliferating cells in luteal tissue; steroidogenic cells were not proliferating. Endothelial cell proliferation varied during the luteal lifespan, with the percent dividing (Ki67-positive) cells highest during luteal development, declining by midluteal phase, and reaching low levels after luteolysis (40, 28, and <5%, respectively). The factors controlling microvascular events in the corpus luteum, including endothelial cell proliferation, are poorly understood. Studies were designed to determine if concepts arising from embryologic models apply to the corpus luteum during the menstrual cycle, i.e., that a balance between vascular endothelial growth factor (VEGF) and the angiopoietins (Ang-1 and its endogenous antagonist, Ang-2) influences the growth, maturation, and destruction of vessels. The results support a novel role of the midcycle gonadotropin surge to stimulate VEGF (protein) and Ang-1 (mRNA) expression in luteinizing granulosa cells of the periovulatory follicle. Moreover, Ang-1 but not VEGF expression may be promoted, at least in part, by LH-induced progesterone production. Following luteal development, levels of VEGF mRNA and protein in luteal cells peak by midluteal phase and decline at luteal regression. In contrast, Ang-2 expression peaks abruptly in the regressing corpus luteum near the end of the cycle. Preliminary data indicate that macaque endothelial cells from the corpus luteum contain VEGF receptors (Flt-1 and KDR) and respond to VEGF in vitro with increased proliferation. Luteal cell-endothelial cell interaction, via the VEGF-/Ang-receptor pathways, may control the microvasculature, and hence development and function of the corpus luteum during the ovarian cycle.