Abstract
BackgroundOvarian angiogenesis is a complex process that is regulated by a balance between pro- and anti-angiogenic factors. Physiological processes within the ovary, such as folliculogenesis, ovulation, and luteal formation are dependent upon adequate vascularization and anything that disrupts normal angiogenic processes may result in ovarian dysfunction, and possibly infertility. The objective of this study was to evaluate the role of the thrombospondin-1 (TSP-1) receptor CD36 in mediating ovarian angiogenesis and regulating ovarian function.MethodsThe role of CD36 was evaluated in granulosa cells in vitro and ovarian morphology and protein expression were determined in wild type and CD36 null mice.ResultsIn vitro, CD36 inhibition increased granulosa cell proliferation and decreased apoptosis. Granulosa cells in which CD36 was knocked down also exhibited an increase in expression of survival and angiogenic proteins. Ovaries from CD36 null mice were hypervascularized, with increased expression of pro-angiogenic vascular endothelial growth factor (VEGF) and its receptor VEGFR-2. Ovaries from CD36 null mice contained an increase in the numbers of pre-ovulatory follicles and decreased numbers of corpora lutea. CD36 null mice also had fewer number of offspring compared to wild type controls.ConclusionsThe results from this study demonstrate that CD36 is integral to the regulation of ovarian angiogenesis by TSP-1 and the expression of these family members may be useful in the control of ovarian vascular disorders.
Highlights
Ovarian angiogenesis is a complex process that is regulated by a balance between pro- and anti-angiogenic factors
TSP-1 and its mimetic peptides have been shown to reduce vascular endothelial growth factor (VEGF) expression, inhibit ovarian angiogenesis, and induce follicle atresia [23,24]. These findings led us to believe that TSP-1 and pro-angiogenic VEGF had reciprocal inhibitory influences in the ovary and we demonstrated that TSP-1 bound VEGF, resulting in its internalization and degradation through the low density lipoprotein receptor related protein (LRP)-1
With the RNA interference, we were able to reduce Spontaneously immortalized rat granulosa cells (SIGC) expression of CD36 by approximately 75% compared to wild type (WT) cells or those transfected with scrambled oligonucleotide sequence (Figure 1A/B)
Summary
Ovarian angiogenesis is a complex process that is regulated by a balance between pro- and anti-angiogenic factors. Physiological processes within the ovary, such as folliculogenesis, ovulation, and luteal formation are dependent upon adequate vascularization and anything that disrupts normal angiogenic processes may result in ovarian dysfunction, and possibly infertility. The objective of this study was to evaluate the role of the thrombospondin-1 (TSP-1) receptor CD36 in mediating ovarian angiogenesis and regulating ovarian function. Ovulation, and formation of the corpus luteum require complex and coordinated interaction of numerous autocrine, paracrine, and endocrine factors to regulate important physiologic processes such as angiogenesis. Reduced expression of TSP-1 is usually associated with aggressive angiogenesis and enhanced tumour formation [7], while TSP-1 over-expression generally results in inhibited tumour formation and reduced tumour vessel density [8]. TSP-1 is typically inversely associated with pro-angiogenic markers such as vascular endothelial growth factor (VEGF) where tumours with a higher TSP-1:VEGF ratio are typically slower growing, while tumours that favor VEGF expression are aggressive and have a higher rate of malignancy [9,10]
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