Delta-9-tetrahydrocannabinol increases vascular endothelial growth factor (VEGF) secretion through a cyclooxygenase-dependent mechanism in rat granulosa cells

While the effects of delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, have been studied extensively in the central nervous system, there is limited knowledge about its effects on the female reproductive system. The aim of this study was to assess the effect of THC on the expression and secretion of the angiogenic factor vascular endothelial growth factor (VEGF) in the ovary, and to determine if these effects were mediated by prostaglandins. Spontaneously immortalized rat granulosa cells (SIGCs) were exposed to THC for 24 h. Gene expression, proliferation and TNFα-induced apoptosis were evaluated in the cells and concentrations of VEGF and prostaglandin E2 (PGE₂), a known regulator of VEGF production, were determined in the media. To evaluate the role of the prostanoid pathway, cells were pre-treated with cyclooxygenase (COX) inhibitors prior to THC exposure. THC-exposed SIGCs had a significant increase in VEGF and PGE₂ secretion, along with an increase in proliferation and cell survival when challenged with an apoptosis-inducing factor. Pre-treatment with COX inhibitors reversed the THC-induced increase in both PGE₂ and VEGF secretion. Alterations in granulosa cell function, such as the ones observed after THC exposure, may impact essential ovarian processes including folliculogenesis and ovulation, which could in turn affect female reproductive health and fertility. With the ongoing increase in cannabis use and potency, further study on the impact of cannabis and its constituents on female reproductive health is required.