Correlation between angiogenic factors and perifollicular blood flow in patients undergoing in vitro fertilization

While primordial and primary follicles receive nutrients and oxygen by passive diffusion from stromal blood vessels, follicular growth is associated with the development of an individual capillary network and continued angiogenesis to nourish the rapidly expanding follicle. It seems, however, that age is negatively correlated with ovarian perifollicular blood flow even if this has been observed only very late in the follicular phase. Support to this finding is the observation of increased levels of Vascular Endothelial Growth Factor (VEGF) in the follicular fluid from aging women. Transcriptional upregulation of VEGF is involved in the cellular adaptation to hypoxia under control of Hypoxia-Inducible Factor 1 (HIF1), a transcription factor activated by low oxygen tension to prevent depletion of oxygen at anoxic levels and subsequent cell death. Various recent studies have discovered that the vascular and the nervous system share an overlapping repertoire of growth factors affecting the development and the homeostasis of both systems. These include members of the vascular endothelial growth factor (VEGF), and neurotrophin growth factor family, such as brain derived neurotrophic factor. It has been shown, in neural tissue, that BDNF activation of TrkB stimulates VEGF mRNA transcription via induction of HIF-1. Thus, in normal tissues, BDNF seems to act as a proangiogenic stimulus. In the ovary, both VEGF and BDNF, secreted by the granulosa cells, seem to play a role in folliculogenesis and oocyte maturation. We aimed at establishing whether there is a relationship between follicular fluid VEGF concentrations, BDNF concentrations and perifollicular blood flow (PFBF) in women undergoing IVF and whether age makes a difference. In a prospective observational study, we enrolled 30 consecutive patients all at their first IVF cycle. These were subdivided in two age groups (13 patients aged 30-34 years and 17 patients aged 35-39 years). At oocyte retrieval, the perifollicular vascularity of one follicle per ovary was estimated qualitatively through power Doppler blood flow, for a total of 60 follicles. The follicular fluid from each of the identified follicles was centrifuged and stored until VEGF and BDNF assay. In our study, we found VEGF levels to be significantly correlated with grade of PFBF only in the younger age group. BDNF did not directly correlate with PFBF in any of the patients. There was a significant positive correlation between VEGF and BDNF follicular fluid levels only in the younger patients. VEGF follicular fluid levels were significantly higher in the older age group than in the younger group (VEGF 955,4 vs 546,5 ng/ml);. BDNF levels were also significantly higher in the older versus younger women undergoing IVF (BDNF 603,3 pg/ml vs 401,1 pg/ml). The ability of a given follicle to express BDNF and VEGF and develop an adequate vascular network may be inter-related. An adequate blood supply is of fundamental importance in the regulation of intrafollicular oxygen levels and the determination of oocyte quality. Reproductive aging may be associated with relatively low levels of intrafollicular oxygen and with an attempt, on behalf of a given follicle, to increase its vascular supply by increasing the secretion of VEGF. The trigger for this phenomenon may be represented by BDNF, which is tightly correlated to VEGF levels in younger age women, and tends to increase in older women.