Fibroblast Growth Factor 2 Is More Dynamic than Vascular Endothelial Growth Factor A During the Follicle-Luteal Transition in the Cow1

Abstract

Luteal inadequacy is a major cause of infertility in a number of species. During the early luteal phase, progesterone production requires the rapid growth of the corpus luteum (CL), which is in turn dependent on angiogenesis. In the present study, we examined the temporal changes in vascular endothelial growth factor A (VEGFA), fibroblast growth factor 2 (FGF2) and secreted protein, acidic, cysteine-rich (osteonectin) (SPARC) during the follicular-luteal transition and CL development in the cow. Luteal VEGFA concentrations increased as the CL developed but were lower in the regressing CL. Conversely, luteal FGF2 concentrations were highest immediately postovulation in the collapsed follicle and declined as the CL developed. Furthermore, three FGF2 isoforms were present in the collapsed follicle, but only one isoform was detected in older CL. Interestingly, FGF2 concentrations increased in the regressing CL. Western blot analysis for SPARC showed the presence of two isoforms, which were constitutively expressed throughout CL development. Further studies investigated the regulation of FGF2 by LH, which showed that FGF2 concentrations in preovulatory follicular fluid were higher in those animals that had experienced an LH surge. Moreover, LH stimulated FGF2 production in dispersed luteal cells. Conversely, the LH surge had no effect on follicular fluid VEGFA concentrations. In conclusion, FGF2 was more dynamic than VEGFA and SPARC during the follicular-luteal transition, which suggests that FGF2 plays a key role in the initiation of angiogenesis at this time. Furthermore, it is likely that this is stimulated by the LH surge. The results also suggest that VEGFA and SPARC have a more constitutive, but essential, role in the development of the CL vasculature.

Mathematical analysis of a model for the growth of the bovine corpus luteum

“…Following (Robinson et al, 2007), we assume that ECs produce FGF2 at a constant rate, a 1 , and LCs produce it at a rate which peaks during the two days that follow ovulation (see Fig 3). Following the disassembly of the theca vasculature after ovulation, extensive proliferation and migration of ECs helps to re-establish connections with other endothelial and luteal cells.…”

“…This coincides Schematic illustration of FGF2 production during CL development. ECs produce FGF2 at constant rate (dotted line) throughout CL development, whereas LCs produce FGF2 for shorter time period (approximately 2 days) but at greater rate ( 4 fold larger) Robinson et al, 2007).…”

“…This is perhaps not surprising, since in several mammals most (up to 85%) of the cells that proliferate during CL growth are ECs (Reynolds and Redmer, 1998). This enables the CL to grow at a rate (0.5 g to ¡5 g in 5 days (Robinson et al, 2007)) that is surpassed only by the fastest growing tumours. Such dramatic growth is essential for the CL to produce sufficient progesterone to support the developing embryo (Robinson et al, 2008).…”

“…In the remainder of this section, we present data taken from (Robinson et al, 2007;Mann, 2009) to motivate the model that we develop. Fig 2(a) shows how the FGF2 concentration in the CL changes in the 12 days that follow oestrous.…”

“…Fig 2(a) shows how the FGF2 concentration in the CL changes in the 12 days that follow oestrous. The surge in FGF2 that occurs during ovulation (days 1-2) (Robinson et al, 2007) is followed by a rapid decrease until FGF2 levels settle to a steady value. The rapid change in FGF2 levels during the two days that proceed ovulation coincides with the initiation of angiogenesis in the early CL.…”